Novel 1,3-dihydro-2h-indol-2-one derivatives, method for preparing same and pharmaceutical compositions containing them

ABSTRACT

The invention relates to compounds of formula:  
                 
 
     and to solvates and/or hydrates thereof, with affinity for and selectivity towards the V 1b  receptors or both the V 1b  and V 1a  receptors of arginine-vasopressin.  
     The invention also relates to a process for preparing them, to the intermediate compounds of formula (II) which are useful for preparing them, to pharmaceutical compositions containing them and to their use for preparing medicinal products.

[0001] The present invention relates to novel 1,3-dihydro-2H-indol-2-onederivatives, to a process for preparing them and to pharmaceuticalcompositions containing them.

[0002] The compounds according to the present invention have affinityfor and selectivity towards the V_(1b) receptors or both the V_(1b) andV_(1a) receptors of arginine-vasopressin (AVP).

[0003] AVP is a hormone which is known for its anti-diuretic effect andits effect in regulating arterial pressure. It stimulates several typesof receptors: V₁ (V_(1a), V_(1b)), V₂. These receptors are located inparticular in the liver, the blood vessels (coronary, renal and cerebralvessels), the platelets, the kidneys, the uterus, the adrenal glands,the pancreas, the central nervous system and the pituitary. AVP thusexerts cardiovascular, hepatic, pancreatic, antidiuretic andplatelet-aggregating effects and effects on the central and peripheralnervous system, and on the uterus.

[0004] The location of the various receptors is described in: S. Jard etal., Vasopressin and oxytocin receptors: an overview, in Progress inEndocrinology, H. Imura and K. Shizurne ed., Experta Medica, Amsterdam,1988, 1183-1188, and in the following articles: J. Lab. Clin. Med.,1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108.

[0005] More particularly, the AVP V_(1a) receptors are located in manyperipheral organs and in the brain. They have been cloned in rats andman and they regulate most of the known effects of AVP: plateletaggregation; uterine contractions; blood vessel contraction; secretionof aldosterone, cortisol, CRF (corticotropin-releasing factor) and ACTH(adrenocorticotrophic hormone); hepatic glycogenolysis, cellproliferation and the main central effects of AVP (hypothermia, memory,etc.).

[0006] The V_(1b) receptors were initially identified in theadenohypophysis of various animal species (rat, pig, cattle, sheep,etc.), including man (S. Jard et al., Mol. Pharmacol., 1986, 30,171-177; Y. Arsenijevic et al., J. Endocrinol., 1994, 141, 383-391; J.Schwartz et al., Endocrinology, 1991, 129 (2), 1107-1109; Y. De Keyseret al., FEBS Letters, 1994, 356, 215-220) in which they stimulate therelease of adenocortico-trophic hormone via AVP and potentiate theeffects of CRF on the release of ACTH (G. E. Gillies et al., Nature,1982, 299, 355). In the hypothalamus, the V_(1b) receptors also induce adirect release of CRF (Neuroendocrinology, 1994, 60, 503-508) and are,in these various respects, involved in stress conditions.

[0007] These V_(1b) receptors have been cloned in rats, man and mice (Y.De Keyser, FEBS Letters, 1994, 356, 215-220; T. Sugimoto et al., J.Biol. Chem., 1994, 269 (43), 27088-27092; M. Saito et al., Biochem.Biophys. Res. Commun., 1995, 212 (3), 751-757; S. J. Lolait et al.,Neurobiology, 1996, 92, 6783-6787; M. A. Ventura et al., Journal ofMolecular endocrinology, 1999, 22, 251-260) and various studies (in situhybridization, PCR (Polymerase Chain Reaction), etc.) reveal theubiquitous presence of these receptors in various central tissues(brain, hypothalamus and adenohypophysis in particular) and peripheraltissues (kidney, pancreas, adrenal glands, heart, lungs, intestine,stomach, liver, mesentery, bladder, thymus, spleen, uterus, retina,thyroid, etc.) and in certain tumours (pituitary, pulmonary, etc.tumours) suggesting a broad biological and/or pathological role forthese receptors and a potential involvement in various diseases.

[0008] By way of example, in rats, studies have shown that AVP regulatesthe endocrine pancreas via the V_(1b) receptors, by stimulating thesecretion of insulin and glucagon (B. Lee et al., Am. J. Physiol. 269(Endocrinol. Metab. 32): E1095-E1100, 1995) or the production ofcatecholamines in the adrenal medullary which is the site of a localsynthesis of AVP (E. Grazzini et al., Endocrinology, 1996, 137 (a),3906-3914). Thus, in the medullary tissue, AVP via these receptors isthought to have a crucial role in certain types of adrenalpheochromocytomas secreting AVP and thereby inducing a sustainedproduction of catecholamines which is the cause of hypertensionconditions that are resistant to angiotensin II receptor antagonists andto conversion enzyme inhibitors. The adrenal cortex is also rich inV_(1a) receptors involved in the production of glucocorticoids andmineralocorticoids (aldosterone and cortisol). Via these receptors, AVP(circulating or synthesized locally) may induce a production ofaldosterone with an efficacy comparable to that of angiotensin II (G.Guillon et al., Endocrinology, 1995, 136 (3), 1285-1295). Cortisol is apowerful regulator of the production of ACTH, the stress hormone.

[0009] Recent studies have also shown that the adrenal glands arecapable of releasing CRF and/or ACTH directly via activation of theV_(1b) and/or V_(1a) receptors borne by the medullary cells (G.Mazzocchi et al., Peptides, 1997, 18 (2), 191-195; E. Grazzini et al.,J. Clin. Endocrinol. Metab., 1999, 84 (6), 2195-2203).

[0010] The V_(1b) receptors are also considered as a marker ofACTH-secreting tumours such as certain pituitary tumours, certainbronchial carcinomas (SCLCs (Small-Cell Lung Cancers)), pancreatic,adrenal and thyroid carcinomas, inducing Cushing's syndrome in certaincases (J. Bertherat et al., Eur. J. Endocrinol., 1996, 135, 173; G. A.Wittert et al., Lancet, 1990, 335, 991-994; G. Dickstein et al., J.Clin. Endorcinol. Metab., 1996, 81 (8), 2934-2941). As regards theV_(1a) receptors, these are a marker more specific for small-cell lungcancers (SCLCs) (P. J. Woll et al., Biochem. Biophys. Res. Commun.,1989, 164 (1), 66-73). Thus, the compounds according to the presentinvention are obvious diagnostic tools and offer a novel therapeuticapproach in the proliferation and detection of these tumours, even at anearly stage (radiolabelling; SPECT (Single Photon Emission ComputedTomography); PET Scan (Positron Emission Tomography Scanner)).

[0011] The abundant presence of the V_(1b) receptor messenger in thestomach and intestine suggests an involvement of AVP via this receptoron the release of gastrointestinal hormones such as choleocystokinin,gastrin or secretin (T. Sugimoto et al., Molecular cloning andfunctional expression of V_(1b) receptor gene, in Neurohypophysis:Recent Progress of Vasopressin and Oxytocin Research; T. Saito, K.Kurokawa and S. Yoshida ed., Elvesier Science, 1995, 409-413).

[0012] 1,3-Dihydro-2H-indol-2-one derivatives have been disclosed incertain patent applications as ligands of the arginine-vasopressinreceptors and/or the ocytocin receptors: mention may be made of patentapplications WO 93/15051, EP 636 608, EP 636 609, WO 95/18105, WO97/15556 and WO 98/25901.

[0013] To date, no non-peptide compound with affinity for andselectivity towards the V_(1b) receptors or both the V_(1b) and V_(1a)receptors of arginine-vasopressin is known.

[0014] Novel 1,3-dihydro-2H-indol-2-one derivatives have now been foundwhich show affinity for and selectivity towards the V_(1b) receptors orboth the V_(1b) and V_(1a) receptors of arginine-vasopressin.

[0015] These compounds may be used to prepare medicinal products thatare useful in treating or preventing any pathology in whicharginine-vasopressin and/or the V_(1b) receptors or both the V_(1b)receptors and the V_(1a) receptors are involved, in particular intreating or preventing complaints of the cardiovascular system, forexample hypertension; of the central nervous system, for example stress,anxiety, depression, obsessive-compulsive disorder and panic attacks; ofthe renal system; of the gastric system, and also in treating small-celllung cancers; obesity; type II diabetes; insulin resistance;hypertriglyceridaemia; atherosclerosis; Cushing's syndrome; anypathology resulting from stress and chronic stress conditions.

[0016] Thus, according to one of its aspects, the present inventionrelates to compounds of formula:

[0017] in which:

[0018] n is 1 or 2;

[0019] W represents an oxygen atom or a sulphur atom; —R₁ represents ahalogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; a trifluoromethylradical; a tri-fluoromethoxy radical;

[0020] R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a(C₁-C₄)alkoxy; a trifluoromethyl radical;

[0021] or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂together represent a trimethylene radical;

[0022] R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy; a trifluoromethoxy radical;

[0023] R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy;

[0024] or R₃ is in position -2- of the phenyl, R₄ is in position -3- ofthe phenyl and R₃ and R₄ together represent a methylenedioxy radical;

[0025] R₅ represents an ethylamino group; a dimethylamino group; a1-azetidinyl radical; a (C₁-C₂)alkoxy;

[0026] R₆ represents a (C₁-C₄)alkoxy;

[0027] R₇ represents a (C₁-C₄)alkoxy;

[0028] as well as the solvates and/or hydrates thereof.

[0029] The compounds of formula (I) comprise at least 2 asymmetriccarbon atoms. The optically pure isomers of the compounds of formula (I)and the mixtures thereof in all proportions form part of the invention.

[0030] The term “halogen atom” means a chlorine, bromine, fluorine oriodine atom.

[0031] The terms “alkyl” and “alkoxy”, respectively, mean a linear orbranched alkyl radical or alkoxy radical, respectively.

[0032] According to the present invention, the compounds of formula (I)that are preferred are those in which:

[0033] n is 1 or 2;

[0034] W represents an oxygen atom or a sulphur atom;

[0035] R₁ represents a halogen atom; a (C₁-C₄)alkyl; a trifluoromethylradical; a tri-fluoromethoxy radical;

[0036] R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a(C₁-C₄)alkoxy; a trifluoromethyl radical;

[0037] or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂together represent a trimethylene radical;

[0038] R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkoxy; atrifluoromethoxy radical;

[0039] R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy;

[0040] or R₃ is in position -2- of the phenyl, R₄ is in position -3- ofthe phenyl and R₃ and R₄ together represent a methylenedioxy radical;

[0041] R₅ represents an ethylamino group; a dimethylamino group; a1-azetidinyl radical; a (C₁-C₂)alkoxy;

[0042] R₆ represents a (C₁-C₄)alkoxy;

[0043] R₇ represents a (C₁-C₄)alkoxy;

[0044] as well as the solvates and/or hydrates thereof.

[0045] According to the present invention, the compounds of formula (I)that are preferred are those in which W represents an oxygen atom.

[0046] According to the present invention, the compounds of formula (I)that are preferred are those in which R₁ represents a chlorine atom, amethyl radical or a trifluoromethoxy radical.

[0047] According to the present invention, the compounds of formula (I)that are preferred are those in which R₂ represents a hydrogen atom, achlorine atom, a fluorine atom, a methyl radical, a methoxy radical or atrifluoromethyl radical; or R₂ is in position -6- of the indol-2-oneand, together with R₁, represents a trimethylene radical.

[0048] According to the present invention, the compounds of formula (I)that are preferred are those in which R₃ represents a chlorine atom, afluorine atom, a hydroxyl, a methoxy radical, an ethoxy radical or atrifluoromethoxy radical.

[0049] According to the present invention, the compounds of formula (I)that are preferred are those in which R₄ represents a hydrogen atom, amethoxy radical or a methyl radical; or R₄ is in position -3- of thephenyl and, together with R₃ in position 2, represents a methylenedioxyradical.

[0050] According to the present invention, the compounds of formula (I)that are preferred are those in which R₅ represents a dimethylaminogroup, an ethylamino group, a 1-azetidinyl radical or a methoxy radical.

[0051] According to the present invention, the compounds of formula (I)that are preferred are those in which R₆ is in position -2- of thephenyl and represents a methoxy radical.

[0052] According to the present invention, the compounds of formula (I)that are preferred are those in which R₇ represents a methoxy radical.

[0053] More particularly, the compounds of formula (I) that arepreferred are those in which:

[0054] n is 1 or 2;

[0055] W represents an oxygen atom;

[0056] R₁ represents a chlorine atom or a methyl radical;

[0057] R₂ represents a hydrogen atom or is in position -6- of theindol-2-one and represents a chlorine atom, a methyl radical, a methoxyradical or a trifluoromethyl radical;

[0058] R₃ is in position -2- of the phenyl and represents a methoxyradical, a chlorine atom or a fluorine atom;

[0059] R₄ represents a hydrogen atom, a methyl radical or a methoxyradical;

[0060] or R₃ is in position -2- of the phenyl, R₄ is in position -3- ofthe phenyl and R₃ and R₄ together represent a methylenedioxy radical;

[0061] R₅ represents a dimethylamino group or a methoxy radical;

[0062] R₆ is in position -2- of the phenyl and represents a methoxyradical;

[0063] R₇ represents a methoxy radical;

[0064] as well as the solvates and/or hydrates thereof.

[0065] According to the present invention, the compounds of formula (I)in the form of optically pure isomers are preferred.

[0066] More particularly, the optically pure isomers of the compounds offormula:

[0067] in which n, W, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are as defined for acompound of formula (I), the carbon atom bearing the substituent C(W)R₅has the (S) configuration and the carbon atom in position 3 of theindol-2-one has either the (R) configuration or the (S) configuration,are preferred.

[0068] Most particularly, the laevorotatory isomer of the compounds offormula (Ia) is preferred.

[0069] The following compounds:

[0070](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0071](2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0072](2S)-1-[6-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0073](2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;

[0074](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0075](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0076](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,6-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0077](2S)-1-[3-(1,3-Benzodioxol-4-yl)-5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0078](2S)-1-[5-Chloro-3-(2-fluorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide, laevorotatoryisomer;

[0079](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxy-6-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0080](2S)-1-[5,6-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0081](2S)-1-[4,5-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0082](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0083](2S)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0084](2S)-1-[5,6-Dimethyl-3-(2-methoxy-6-methyl-phenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;

[0085](2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;

[0086](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;

[0087](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;

[0088] as well as the solvates and/or hydrates thereof, are moreparticularly preferred.

[0089] According to another of its aspects, a subject of the presentinvention is a process for preparing the compounds of formula (I),solvates thereof and/or hydrates thereof, characterized in that:

[0090] a compound of formula:

[0091] in which n, W, R₁, R₂, R₃, R₄ and R₅ are as defined for acompound of formula (I), is reacted, in the presence of a base, with ahalide of formula:

[0092] in which R₆ and R₇ are as defined for a compound of formula (I)and Hal represents a halogen atom.

[0093] The reaction is carried out in the presence of a strong base, forinstance a metal hydride such as sodium hydride or an alkali metalalkoxide such as potassium tert-butoxide, in an anhydrous solvent suchas N,N-dimethylformamide or tetrahydrofuran and at a temperature ofbetween −70° C. and +60° C. The reaction is preferably carried out usinga compound of formula (III) in which Hal=Cl.

[0094] According to one variant of the process and when R₅ represents anethylamino group, a dimethylamino group or a 1-azetidinyl radical and Wrepresents an oxygen atom:

[0095] a) a compound of formula:

[0096] in which n, R₁, R₂, R₃ and R₄ are as defined for a compound offormula (I), is reacted, in the presence of a base, with a halide offormula:

[0097] in which R₆ and R₇ are as defined for a compound of formula (I),to give a compound of formula:

[0098] b) the compound of formula (I′) is hydrolysed by the action of anacid to give a compound of formula:

[0099] c) the compound of formula (I″) is reacted with ethylamine,dimethylamine or azetidine.

[0100] In step a), the reaction between the compound of formula (II′)and the halide of formula (III) is carried out as described above forthe process according to the invention.

[0101] The compound of formula (I′) thus obtained is hydrolysed in stepb) with a strong acid such as hydrochloric acid in an inert solvent suchas dioxane and at a temperature of between 0° C. and room temperature.

[0102] In step c), the reaction between the compound of formula (I″) andethylamine, dimethylamine or azetidine is carried out in the presence ofa coupling agent used in peptide chemistry, such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphateor benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate inthe presence of a base such as triethylamine orN,N-diisopropylethylamine, in an inert solvent such as dichloromethane,tetrahydrofuran or a mixture of these solvents, and at a temperature ofbetween 0° C. and room temperature.

[0103] In particular, a compound of formula (I) in which R₃ representshydroxyl is prepared by reacting a compound of formula (II) in which R₃represents a benzyloxy group with a compound of formula (III) accordingto the process of the invention. The compound thus obtained is thendeprotected according to the method described in Chem. Pharm. Bull.,1978, 26 (8), 2562-2564 to give the expected compound of formula (I).

[0104] The compounds of formula (I) thus obtained may be subsequentlyseparated from the reaction medium and purified according to theconventional methods, for example by crystallization or chromatography.

[0105] The compounds of formula (II) or (II′) are prepared by reacting a3-halo-1,3-dihydro-2H-indol-2-one compound of formula:

[0106] in which R₁, R₂, R₃ and R₄ are as defined for a compound offormula (I) and Hal represents a halogen atom, preferably chlorine orbromine, with a compound of formula:

[0107] in which n, W and R₅ are as defined for a compound of formula(I). The reaction is carried out in the absence or presence of a basesuch as diisopropylethylamine or triethylamine, in an inert solvent suchas dichloromethane, chloroform, tetrahydrofuran, methanol or a mixtureof these solvents and at a temperature of between 0° C. and the refluxtemperature of the solvent. In the absence of base, the reaction iscarried out using an excess of the compound of formula (V) or (V′).

[0108] The compounds of formula (III) are known or prepared by knownmethods such as those disclosed in EP-0 469 984 B and WO 95/18105. Forexample, the compounds of formula (III) may be prepared by halogenationof the corresponding benzenesulphonic acids or of their salts, forexample of their sodium or potassium salts. The reaction is carried outin the presence of a halogenating agent such as phosphorus oxychloride,thionyl chloride, phosphorus trichloride, phosphorus tribromide orphosphorus pentachloride, without solvent or in an inert solvent such asa halogenated hydrocarbon or N,N-dimethylformamide and at a temperatureof between −10° C. and 200° C.

[0109] 2,4-Dimethoxybenzenesulphonyl chloride is prepared according toJ. Am. Chem. Soc., 1952, 74, 2008. 3,4-Dimethoxybenzenesulphonylchloride is commercially available, or is prepared according to J. Med.Chem., 1977, 20 (10), 1235-1239.

[0110] The compounds of formula (IV) are known and are preparedaccording to known methods such as those disclosed in WO 95/18105.

[0111] For example, a compound of formula:

[0112] in which R₁, R₂, R₃ and R₄ are as defined for a compound offormula (I), is converted into a compound of formula (IV) in whichHal=Cl by the action of thionyl chloride in the presence of a base suchas pyridine, in an inert solvent such as dichloromethane and at atemperature of between 0° C. and room temperature.

[0113] According to another example of the preparation of the compoundsof formula (IV), a compound of formula:

[0114] in which R₁, R₂, R₃ and R₄ are as defined for a compound offormula (I), is converted into a compound of formula (IV) in whichHal=Br, using a halogenating agent such as bromine according to theprocess described in Farm. Zh. (Kiev), 1976, 5, 30-33.

[0115] The compounds of formula (VI) are known and are preparedaccording to known methods such as those disclosed in WO 95/18105.

[0116] For example, a compound of formula (VI) is prepared by reacting a1H-indole-2,3-dione derivative of formula:

[0117] in which R₁ and R₂ are as defined for a compound of formula (I),with an organomagnesium derivative of formula:

[0118] in which R₃ and R₄ are as defined for a compound of formula (I)and Hal represents a halogen atom, preferably bromine or iodine, in aninert solvent such as tetrahydrofuran or diethyl ether and at atemperature of between 0° C. and the reflux temperature of the solvent.

[0119] A compound of formula (VI) in which R₃ is as defined for acompound of formula (I) and is in position -2- of the phenyl and R₄,which is other than hydrogen, is in position -3- or -6- of the phenyl,may also be prepared by reacting a compound of formula:

[0120] in which R₃ is as defined for a compound of formula (I) and R₄ isin position -2- or -5- of the phenyl, with a lithium derivative such asn-butyllithium, and the lithiated intermediate thus obtained is thenreacted with a compound of formula (VIII). The reaction is carried outin a solvent such as diethyl ether, tetrahydrofuran, hexane or a mixtureof these solvents, at a temperature of between −70° C. and roomtemperature.

[0121] The 1H-indole-2,3-dione derivatives (VIII) are commerciallyavailable or are prepared according to the methods described inTetrahedron Letters, 1998, 39, 7679-7682; Tetrahedron Letters, 1994, 35,7303-7306; J. Org. Chem., 1977, 42 (8), 1344-1348; J. Org. Chem., 1952,17, 149-156; J. Am. Chem. Soc., 1946, 68, 2697-2703; Organic Syntheses,1925, V, 71-74 and Advances in Heterocyclic Chemistry, A. R. Katritzkyand A. J. Boulton, Academic Press, New York, 1975, 18, 2-58.

[0122] The organomagnesium derivatives (IX) are prepared according tothe conventional methods that are well known to those skilled in theart.

[0123] A compound of formula (VI) may also be prepared by atmosphericoxidation of a compound of formula (VII) in the presence of a base suchas sodium hydride and in the presence of dimethyl disulphide.

[0124] In particular, the compounds of formula (VI) in which R₃ is inposition -2 of the phenyl and R₃=(C₁-C₂)alkoxy and R₄=H, orR₃=R₄=(C₁-C₂)alkoxy with R₄ in position -3 or -6 of the phenyl, R₂ isother than a halogen atom and R₁ is as defined for a compound of formula(I), may be prepared by following the process described in Scheme 1.

[0125] In step a1 of Scheme 1, a compound of formula (X) is firstreacted with a lithium derivative such as n-butyllithium, in the absenceor presence of a base such as N,N,N′,N′-tetramethylethylenediamine, andthe lithiated intermediate thus obtained is then reacted with diethyloxalate to give the compound of formula (XI). The reaction is carriedout in an inert solvent such as diethyl ether, tetrahydrofuran, hexaneor a mixture of these solvents and at a temperature of between −70° C.and room temperature.

[0126] In step b1, a compound of formula (XII) is first reacted with twoequivalents of a lithium derivative such as tert-butyllithium, and thelithiated derivative thus obtained is then reacted with the compound offormula (XI) to give the expected compound of formula (VI). The reactionis carried out in an inert solvent such as diethyl ether,tetrahydrofuran, pentane or a mixture of these solvents and at atemperature of between −70° C. and room temperature.

[0127] The compounds of formula (X) are commercially available or aresynthesized conventionally.

[0128] The compounds of formula (XII) are prepared by reacting thecorresponding aniline derivatives with di-tert-butyl dicarbonateaccording to the conventional methods.

[0129] The compounds of formula (VII) are known and are preparedaccording to known methods such as those disclosed in WO 95/18105 or inJ. Org. Chem., 1968, 33, 1640-1643.

[0130] The compounds of formula (V) are known or are prepared accordingto known methods. Thus, for example, the compounds of formula (V) inwhich W represents an oxygen atom and R₅ represents an ethylamino ordimethylamino group or a 1-azetidinyl radical are prepared according toScheme 2 below in which Pr represents an N-protecting group, inparticular tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl and n is asdefined for a compound of formula (I).

[0131] In step a2 of Scheme 2, the nitrogen atom of the compound offormula (XIII) is protected according to the conventional methods togive a compound of formula (XIV). Some of the compounds of formula (XIV)are commercially available.

[0132] The acid (XIV) is reacted in step b2 with ethylamine,dimethylamine or azetidine according to the conventional methods ofpeptide coupling to give the compound of formula (XV), which isdeprotected in step c2, according to the known methods, to give theexpected compound of formula (V). In particular, when Pr represents a9-fluorenylmethoxycarbonyl group, the deprotection is carried out usingthe method described in Synthetic Communications, 1994, 24 (2), 187-195.

[0133] The compounds of formula (V) in which R₅ represents a(C₁-C₂)alkoxy or the compounds of formula (V′) are known or are preparedaccording to known methods such as, for example, by esterificationreaction starting with the acids of formula (XIII).

[0134] The acids of formula (XIII) are commercially available.

[0135] The compounds of formula (V) in which W represents a sulphur atomare prepared from the corresponding compounds of formula (V) in which Wrepresents an oxygen atom, N-protected on the nitrogen atom, using themethods described in J. Med. Chem., 1989, 2178-2199, in particular byreaction with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulphide orwith phosphorus pentasulphide. After a step of deprotection of thenitrogen atom, the expected compound of formula (V) is obtained.

[0136] When it is desired to prepare an optically pure compound offormula (I), an optically pure compound of formula (II) or (II′) ispreferably reacted according to the process of the invention or thevariant of the process.

[0137] The optically pure compounds of formula (II) or (II′) areprepared by reacting the racemic compound of formula (IV) with anoptically pure compound of formula (V) or (V′), followed by separationof the mixture of diastereoisomers according to the conventionalmethods, for example by crystallization or chromatography.

[0138] Alternatively, the mixture of diastereoisomers of the compound offormula (II) or (II′) may be reacted and the mixture of diastereoisomersof the compound of formula (I) thus obtained may be separated.

[0139] During any one of the steps for preparing the compounds offormula (I) or the intermediate compounds of formula (II), (II′), (IV),(V), (V′) or (VI), it may be necessary and/or desirable to protect thereactive or sensitive functional groups, such as the amine, hydroxyl orcarboxyl groups, present on any one of the molecules concerned. Thisprotection may be carried out using the conventional protecting groups,such as those described in Protective Groups in Organic Chemistry, J. F.W. McOmie, Ed. Plenum Press, 1973, in Protective Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wutts, Ed. John Wiley and Sons,1991 or in Protecting Groups, Kocienski P. J., 1994, Georg ThiemeVerlag. The protecting groups may be removed by a suitable subsequentstep using the methods known to those skilled in the art which do notaffect the rest of the molecule concerned.

[0140] The N-protecting groups which may be used are the conventionalN-protecting groups that are well known to those skilled in the art,such as, for example, the tert-butoxycarbonyl, fluorenylmethoxycarbonyl,benzyl, benzhydrylidene or benzyloxycarbonyl group.

[0141] The compounds of formula (II) are novel and form part of theinvention.

[0142] Thus, according to another of its aspects, a subject of theinvention is compounds of formula:

[0143] in which:

[0144] n is 1 or 2;

[0145] W represents an oxygen atom or a sulphur atom;

[0146] R₁ represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; atrifluoromethyl radical; a tri-fluoromethoxy radical;

[0147] R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a(C₁-C₄)alkoxy; a trifluoromethyl radical;

[0148] or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂together represent a divalent trimethylene radical;

[0149] R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy; a trifluoromethoxy radical;

[0150] R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy;

[0151] or R₃ is in position -2- of the phenyl, R₄ is in position -3- ofthe phenyl and R₃ and R₄ together represent a methylenedioxy radical;

[0152] R₅ represents an ethylamino group; a dimethylamino group; a1-azetidinyl radical; a (C₁-C₂)alkoxy; as well as the salts thereof withmineral or organic acids, in the form of optically pure isomers or inthe form of a mixture of diastereoisomers or in the form of a racemicmixture.

[0153] The salts of the compounds of formula (II) comprise those withmineral or organic acids which allow a suitable separation orcrystallization of the compounds of formula (II) such as thehydrochloride, the hydrobromide, the oxalate, the maleate, thesuccinate, the fumarate, the citrate or the acetate.

[0154] The above compounds of formula (I) also comprise those in whichone or more hydrogen or carbon atoms have been replaced with theirradioactive isotope, for example tritium, or carbon-14. Such labelledcompounds are useful in research, metabolism or pharmacokinetics studiesand in biochemical assays as receptor ligands.

[0155] The compounds according to the invention have undergonebiochemical studies.

[0156] The affinity of the compounds of formula (I) according to theinvention for arginine-vasopressin V_(1b) receptors was determined invitro using the method described by Y. De Keyser et al., FEBS Letters,1994, 356, 215-220. This method consists in studying in vitro thedisplacement of tritiated arginine-vasopressin ([³H]-AVP) at the V_(1b)receptors present on adenohypophysal membrane or cell preparationscarrying rat or human V_(1b) receptors. The 50% inhibitoryconcentrations (IC₅₀) for the attachment of tritiatedarginine-vasopressin of the compounds according to the invention are lowand vary from 10⁻⁷ to 10⁻⁹ M.

[0157] The affinity of the compounds of formula (I) according to theinvention for arginine-vasopressin V_(1a) receptors was determined invitro using the method described by M. Thibonnier et al., J. Biol.Chem., 1994, 269, 3304-3310. This method consists in studying in vitrothe displacement of tritiated arginine-vasopressin ([³H]-AVP) at theV_(1a) receptors present on membrane or cell preparations carrying rator human V_(1a) receptors Some of the compounds of formula (I) alsoexhibit an affinity for arginine-vasopressin V_(1a) receptors, with IC₅₀values which vary from 10⁻⁷ to 10⁻⁹ M.

[0158] The affinity of the compounds of formula (I) according to theinvention for vasopressin V₂ receptors has also been studied (methoddescribed by M. Birnbaumer et al., Nature (Lond.), 1992, 357, 333-335).The compounds studied have little or no affinity for the V₂ receptors,with IC₅₀ values which are generally greater than 10⁻⁶ M.

[0159] The compounds of the present invention are in particular activeprinciples of pharmaceutical compositions, the toxicity of which iscompatible with their use as medicaments.

[0160] According to another of its aspects, the present inventionrelates to the use of the compounds of formula (I), of their solvatesand/or of their hydrates which are pharmaceutically acceptable for thepreparation of medicaments intended for the treatment of any pathologywhere arginine-vasopressin and/or its V_(1b) receptors or both itsV_(1b) receptors and its V_(1a) receptors are implicated.

[0161] According to another of its aspects, the present inventionrelates to the use of the compounds of formula (I), of their solvatesand/or of their hydrates which are pharmaceutically acceptable for thepreparation of medicaments intended for the treatment of pathologies ofthe cardiovascular system, of the central nervous system, of the renalsystem or of the gastric system and of small-cell lung cancers, obesity,type II diabetes, insulin resistance, hypertriglyceridaemia,atherosclerosis, Cushing's syndrome or any pathology resulting fromstress and chronic stress conditions.

[0162] Thus, the compounds according to the invention may be used, inman or in animals, in the treatment or prevention of variousvasopressin-dependent conditions, such as cardiovascular conditions, forexample hypertension, pulmonary hypertension, cardiac insufficiency,myocardial infarction or coronary vasospasm, in particular in smokers,Raynaud's syndrome, unstable angina and PTCA (percutaneous transluminalcoronary angioplasty), cardiac ischaemia or haemostasis disturbances;conditions of the central nervous system, such as migraine, cerebralvasospasm, cerebral haemorrhage, cerebral oedema, depression, anxiety,stress, obsessive-compulsive disorder, panic attacks, psychotic statesor memory disorders, for example; conditions of the renal system, suchas renal vasospasm, necrosis of the renal cortex or nephrogenic diabetesinsipidus; conditions of the gastric system, such as gastric vasospasm,cirrhosis of the liver, ulcers or the pathology of vomiting, for examplenausea, including nausea due to chemotherapy or travel sickness; ordiabetic nephropathy. The compounds according to the invention can alsobe used in the treatment of disorders of sexual behaviour; in women, thecompounds according to the invention can be used to treat dysmenorrhoeaor premature labour. The compounds according to the invention can alsobe used in the treatment of small-cell lung cancers; hyponatremicencephalopathy; pulmonary syndrome; Meniere's disease; glaucoma;cataracts; obesity; type II diabetes; atherosclerosis; Cushing'ssyndrome; insulin resistance; or hypertriglyceridaemia; or inpost-operative treatments, in particular after abdominal surgery.

[0163] The compounds according to the invention can also be used in thetreatment or prevention of any pathology resulting from stress, such asfatigue and its syndromes, ACTH-dependent disorders, cardiac disorders,pain, modifications in gastric emptying, in faecal excretion (colitis,irritable bowel syndrome or Crohn's disease) or in acid secretion,hyperglycaemia, immunosuppression, inflammatory processes (rheumatoidarthritis and osteoarthritis), multiple infections, cancers, asthma,psoriasis, allergies and various neuropsychiatric disorders, such asanorexia nervosa, bulimia, mood disorders, depression, anxiety, sleepdisorders, panic states, phobias, obsession, disorders of painperception (fibromyalgia), neurodegenerative diseases (Alzheimer'sdisease, Parkinson's disease or Huntington's disease), substancedependence, haemorrhagic stress, muscle spasms or hypoglycaemia. Thecompounds according to the invention can also be used in the treatmentor prevention of chronic stress conditions, such as immunodepression,fertility disorders or dysfunctionings of thehypothalamopituitary-adrenal axis.

[0164] The compounds according to the invention can also be used aspsychostimulants, resulting in an increase in alertness or emotionalreactivity to the surroundings and making adaptation easier.

[0165] The above compounds of formula (I), their solvates and/or theirhydrates which are pharmaceutically acceptable can be used at dailydoses of 0.01 to 100 mg per kilo of body weight of the mammal to betreated, preferably at daily doses of 0.1 to 50 mg/kg. In man, the dosecan preferably vary from 0.1 to 4 000 mg per day, more particularly from0.5 to 1 000 mg, depending upon the age of the subject to be treated orthe type of treatment: prophylactic or curative.

[0166] For their use as medicaments, the compounds of formula (I) aregenerally administered in dosage units. The said dosage units arepreferably formulated in pharmaceutical compositions in which the activeprinciple is mixed with one or more pharmaceutical excipients.

[0167] Thus, according to another of its aspects, the present inventionrelates to pharmaceutical compositions including, as active principle, acompound of formula (I), one of its solvates and/or one of its hydrateswhich are pharmaceutically acceptable.

[0168] In the pharmaceutical compositions of the present invention foradministration by the oral, sublingual, inhaled, subcutaneous,intramuscular, intravenous, transdermal, local or rectal route, theactive principles can be administered in single-dose administrationforms, as a mixture with conventional pharmaceutical vehicles, toanimals and human beings. The appropriate single-dose administrationforms comprise forms by the oral route, such as tablets, gelatincapsules, powders, granules and oral solutions or suspensions,sublingual and buccal administration forms, aerosols, topicaladministration forms, implants, subcutaneous, intramuscular,intravenous, intranasal or intraocular administration forms and rectaladministration forms.

[0169] When a solid composition is prepared in the form of tablets orgelatin capsules, a mixture of pharmaceutical excipients is added to themicronized or nonmicronized active principle, which mixture can becomposed of diluents, such as, for example, lactose, microcrystallinecellulose, starch or dicalcium phosphate, of binders, such as, forexample, polyvinylpyrrolidone or hydroxypropylmethylcellulose, ofdisintegrating agents, such as crosslinked polyvinylpyrrolidone orcrosslinked carboxymethylcellulose, of flow agents, such as silica ortalc, or of lubricants, such as magnesium stearate, stearic acid,glyceryl tribehenate or sodium stearylfumarate.

[0170] Wetting agents or surfactants, such as sodium lauryl sulphate,polysorbate 80 or poloxamer 188, can be added to the formulation.

[0171] The tablets can be prepared by various techniques: directtabletting, dry granulation, wet granulation or hot-melt.

[0172] The tablets can be bare or sugar-coated (with sucrose, forexample) or coated with various polymers or other appropriate materials.

[0173] The tablets can have a flash, delayed or sustained release bypreparing polymeric matrices or by using specific polymers when formingthe thin film.

[0174] The gelatin capsules may be soft or hard and may or may not becoated with a thin film, so as to have a flash, sustained or delayedactivity (for example via an enteric form).

[0175] They can comprise not only a solid formulation formulated asabove for tablets but also liquids or semi-solids.

[0176] A preparation in the form of a syrup or elixir can comprise theactive principle in conjunction with a sweetener, preferably acalorie-free sweetener, methylparaben and propylparaben, as antiseptic,a flavouring agent and an appropriate colorant.

[0177] The water-dispersible powders or granules can comprise the activeprinciple as a mixture with dispersing agents, wetting agents orsuspending agents, such as polyvinylpyrrolidone, as well as withsweeteners or flavour enhancers.

[0178] For rectal administration, recourse is had to suppositories whichare prepared with binders which melt at the rectal temperature, forexample cocoa butter or polyethylene glycols.

[0179] For parenteral, intranasal or intraocular administration, use ismade of aqueous suspensions, isotonic saline solutions or sterile andinjectable solutions which comprise pharmacologically compatibledispersing agents and/or solubilizing agents, for example propyleneglycol.

[0180] Thus, to prepare an aqueous solution which can be injected by theintravenous route, use may be made of a cosolvent, such as, for example,an alcohol, such as ethanol, or a glycol, such as polyethylene glycol orpropylene glycol, and of a hydrophilic surfactant, such as polysorbate80 or poloxamer 188. To prepare an oily solution which can be injectedby the intramuscular route, the active principle can be dissolved with atriglyceride or a glyceryl ester.

[0181] For local administration, use may be made of creams, ointments,gels, eyewashes or sprays.

[0182] For transdermal administration, use may be made of patches inmultilaminar or reservoir form, in which the active principle can be inalcoholic solution, or sprays.

[0183] For administration by inhalation, use is made of an aerosolcomprising, for example, sorbitan trioleate or oleic acid andtrichlorofluoromethane, dichlorofluoromethane,dichlorotetrafluoroethane, freon substitutes or any other biologicallycompatible propellant gas; use may also be made of a system comprisingthe active principle, alone or in combination with an excipient, inpowder form.

[0184] The active principle can also be presented in the form of acomplex with a cyclodextrin, for example α-, β- or γ-cyclodextrin or2-hydroxypropyl-β-cyclodextrin.

[0185] The active principle can also be formulated in the form ofmicrocapsules or microspheres, optionally with one or more vehicles oradditives.

[0186] Use may be made of implants among the sustained-release forms ofuse in the case of chronic treatments. These implants can be prepared inthe form of an oily suspension or in the form of a suspension ofmicrospheres in an isotonic medium.

[0187] The active principle of formula (I) is present in each dosageunit in the amounts suited to the daily doses envisaged. In general,each dosage unit is suitably adjusted according to the dosage and thetype of administration provided, for example tablets, gelatin capsulesand the like, sachets, blisters, syrups and the like, or drops, so thatsuch a dosage unit comprises from 0.1 to 1 000 mg of active principle,preferably from 0.5 to 250 mg, which has to be administered one to fourtimes daily.

[0188] Although these dosages are examples of average situations, theremay be specific cases where higher or lower dosages are appropriate;such dosages also form part of the invention. According to the usualpractice, the dosage appropriate to each patient is determined by thephysician according to the method of administration and the age, theweight and the response of the said patient.

[0189] The compositions of the present invention can comprise, inaddition to the compounds of formula (I), their solvates and/or theirhydrates which are pharmaceutically acceptable, other active principleswhich can be of use in the treatment of the disorders or diseasesindicated above.

[0190] Thus, another subject-matter of the present invention ispharmaceutical compositions comprising several active principles incombination, one of which is a compound according to the invention.

[0191] Thus, according to the present invention, pharmaceuticalcompositions can be prepared which comprise a compound according to theinvention in combination with a compound which has an effect on the CRFreceptors.

[0192] The compounds according to the invention can also be used for thepreparation of compounds for veterinary use.

[0193] The following PREPARATIONS and EXAMPLES illustrate the inventionwithout, however, limiting it.

[0194] Use is made, in the Preparations and in the Examples, of thefollowing abbreviations:

[0195] ether: diethyl ether

[0196] iso ether: diisopropyl ether

[0197] DMF: N,N-dimethylformamide

[0198] THF: tetrahydrofuran

[0199] DCM: dichloromethane

[0200] EtOAc: ethyl acetate

[0201] TMEDA: N,N,N′,N′-tetramethylethylenediamine

[0202] DIPEA: diisopropylethylamine

[0203] TFA: trifluoroacetic acid

[0204] Boc: tert-butoxycarbonyl

[0205] Cbz: benzyloxycarbonyl

[0206] Bzl: benzyl

[0207] BOP: benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate

[0208] PyBOP: benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate

[0209] DCC: 1,3-dicyclohexylcarbodiimide

[0210] HOBT: 1-hydroxybenzotriazole hydrate

[0211] Ethyl ether: saturated solution of hydrogen chloride in diethylether

[0212] M.p.: melting point

[0213] RT: room temperature

[0214] B.p.: boiling point

[0215] HPLC: high performance liquid chromatography.

[0216] The proton magnetic resonance spectra (¹H NMR) are recorded at200 MHz in d₆-DMSO using the d₆-DMSO peak as reference. The chemicalshifts 6 are expressed in parts per million (ppm). The signals observedare expressed thus: s: singlet; bs: broad singlet; d: doublet; dd:doubled doublet; t: triplet; dt: doubled triplet; q: quartet; up:unresolved peak; mt: multiplet.

[0217] Preparations

[0218] Preparations of the compounds of formula (IV).

[0219] Preparation 1.1

[0220] 3,5-Dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one.

[0221] (IV): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=H; Hal=Cl

[0222] A)5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0223] This compound is prepared according to the procedure disclosed inWO 95/18105. A solution of 2-methoxyphenylmagnesium bromide is preparedfrom 16 g of magnesium in 35 ml of ether and from a solution of 124 g of1-bromo-2-methoxybenzene in 175 ml of ether. This solution is addeddropwise under an argon atmosphere to a mixture, cooled beforehand in anice bath, of 30 g of 5-chloro-1H-indole-2,3-dione in 250 ml of THF andthen the mixture is left stirring while allowing the temperature to riseto RT. After stirring for 1 hour at RT, the reaction mixture is slowlypoured into saturated NH₄Cl solution and the THF is evaporated off undervacuum. The precipitate formed is spin-filtered off and is washed withiso ether. 42 g of the expected product are obtained, which product isused without further purification in the following stage.

[0224] B) 3,5-Dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0225] This compound is prepared according to the procedure disclosed inWO 95/18105. A mixture of 9 g of the compound obtained in the precedingstage and 3.74 ml of pyridine in 100 ml of DCM is cooled to 0° C., asolution of 3.45 ml of thionyl chloride in 3 ml of DCM is added dropwiseover 3 minutes, and the mixture is left stirring for 30 minutes. Wateris added to the reaction mixture and the DCM is evaporated off undervacuum at RT. The precipitate formed is spin-filtered off, washed fourtimes with water and then with cold iso ether, and dried. 8.8 g of theexpected product are obtained.

[0226] Preparation 1.2

[0227] 3,5-Dichloro-3-(2-ethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0228] (IV): R₁=Cl; R₂=H; R₃=2-OCH₂CH₃; R₄=H; Hal=Cl

[0229] A) 1-Bromo-2-ethoxybenzene

[0230] A mixture of 17.5 g of 2-bromophenol, 66 ml of diethyl sulphateand 170 ml of 10% NaOH solution is refluxed for 2 hours. After coolingthe reaction mixture to RT, it is extracted with EtOAc, the organicphase is washed with 2N NaOH solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. 19.6 g of the expected productare obtained.

[0231] B)5-Chloro-3-(2-ethoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

[0232] A solution of 2-ethoxyphenylmagnesium bromide is prepared from2.2 g of magnesium in 10 ml of ether and from a solution of 16.5 g ofthe compound obtained in the preceding step in 40 ml of ether. Thissolution is added dropwise, under a nitrogen atmosphere, to a mixture of5 g of 5-chloro-1H-indole-2,3-dione in 20 ml of THF, while keeping thetemperature of the reaction medium below 35° C. After stirring for 2hours at RT, the reaction mixture is poured into 200 ml of 2N HCl andextracted with EtOAc, the organic phase is dried over Na₂SO₄ and thesolvents are evaporated off under vacuum. The residue is taken up in hotiso ether and left to recrystallize. The crystalline product formed isspin-filtered off, washed with iso ether and dried. 5.7 g of theexpected product are obtained; m.p.=251° C.

[0233] C) 3,5-Dichloro-3-(2-ethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0234] 1 ml of thionyl chloride is added at RT to a mixture of 3 g ofthe compound obtained in the preceding step and 2 ml of pyridine in 50ml of DCM, and the mixture is left stirring for 1 hour at RT. Thereaction mixture is chromatographed on silica gel, eluting with DCM. 2.4g of the expected product are obtained after crystallization from isoether; m.p.=198° C.

[0235] Preparation 1.3

[0236] 3,5-Dichloro-3-(3-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0237] (IV): R₁=Cl; R₂=H; R₃=3-OCH₃; R₄=H; Hal=Cl

[0238] A)5-Chloro-3-hydroxy-3-(3-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0239] A solution of 3-methoxyphenylmagnesium bromide is prepared from3.5 g of magnesium in 10 ml of THF and from a solution of 25 g of1-bromo-3-methoxy-benzene in 40 ml of THF. This solution is addeddropwise, under a nitrogen atmosphere, to a mixture of 8 g of5-chloro-1H-indole-2,3-dione in 50 ml of THF, while keeping thetemperature of the reaction medium below 40° C., followed by refluxingfor 1 hour. The reaction mixture is cooled to RT, poured into saturatedNH₄Cl solution and extracted with EtOAc, the organic phase is washedwith water and dried over Na₂SO₄, and the solvent is evaporated offunder vacuum. 9.1 g of the expected product are obtained aftercrystallization from hot iso ether; m.p.=212° C.

[0240] B) 3,5-Dichloro-3-(3-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0241] A mixture of 5 g of the compound obtained in the preceding stepand 2 ml of pyridine in 20 ml of DCM is cooled to a temperature below10° C., a solution of 1.65 ml of thionyl chloride in 10 ml of DCM isadded dropwise and the mixture is left stirring for 30 minutes at RT.The reaction mixture is washed twice with water, the organic phase isdried over Na₂SO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with DCM. 3.1 g of theexpected product are obtained; m.p.=170° C.

[0242] Preparation 1.4

[0243] 3,5-Dichloro-3-(4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0244] (IV): R₁=Cl; R₂=H; R₃=4-OCH₃; R₄=H; Hal=Cl

[0245] A)5-Chloro-3-hydroxy-3-(4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0246] This compound is prepared according to the procedure described instep A of Preparation 1.3 starting with 3.5 g of magnesium, 25 g of1-bromo-4-methoxybenzene, 50 ml of THF and a mixture of 8 g of5-chloro-1H-indol-2,3-dione in 50 ml of THF. 9.3 g of the expectedproduct are obtained after crystallization from hot iso ether; m.p.=202°C.

[0247] B) 3,5-Dichloro-3-(4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0248] 0.9 ml of thionyl chloride is added to a mixture of 2.5 g of thecompound obtained in the preceding step and 1 ml of pyridine in 30 ml ofDCM at a temperature below 20° C., and the mixture is left stirring for15 minutes. The reaction mixture is washed twice with water and driedover Na₂SO₄, and this solution is used without further purification inPreparations 3.9 and 3.10.

[0249] Preparation 1.5

[0250] 3,5-Dichloro-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0251] (IV): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=3-OCH₃; Hal=Cl

[0252] A) Ethyl 2-(2,3-dimethoxyphenyl)-2-oxoacetate

[0253] A mixture of 27.6 g of 1,2-dimethoxybenzene in 160 ml of ether iscooled to −40° C., 250 ml of a 1.6 M solution of n-butyllithium inhexane are added dropwise and the mixture is then left stirring for 24hours while allowing the temperature to return to RT. The reactionmixture is cooled to −20° C., 136 ml of diethyl oxalate are addedrapidly and the mixture is left stirring while allowing the temperatureto return to RT. After stirring for 30 minutes at RT, the reactionmixture is poured into saturated NH₄Cl solution, the phases areseparated after settling has taken place, the aqueous phase is extractedwith ether, the combined organic phases are washed twice with water anddried over Na₂SO₄, and the solvents are evaporated off under vacuum. Theexcess diethyl oxalate is removed by distillation under vacuum (b.p.=90°C. at 2 400 Pa). The resulting crude product is chromatographed onsilica gel, eluting with a heptane/iso ether mixture (90/10; v/v). 25 gof the expected product are obtained and are used without furtherpurification in the following step.

[0254] B)5-Chloro-3-hydroxy-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0255] a) tert-Butyl 4-chlorophenylcarbamate

[0256] A mixture of 12.7 g of 4-chloroaniline and 22 g of di-tert-butyldicarbonate in 60 ml of dioxane is left stirring for 24 hours at RT. Thereaction mixture is concentrated under vacuum, the residue is taken upin pentane and the precipitate formed is spin-filtered off and dried.22.5 g of the expected product are obtained.

[0257] b) A mixture of 11.4 g of tert-butyl

[0258] 4-chlorophenylcarbamate in 100 ml of ether is cooled to −40° C.under an atmosphere of dry nitrogen, 80 ml of a 1.5 M solution oftert-butyllithium in pentane are added dropwise and the mixture is leftstirring at −20° C. for 3 hours. The reaction mixture is cooled to −40°C., a solution-of 14 g of the compound obtained in step A in 50 ml ofTHF is added over 1 hour and the mixture is left stirring for 4 days atRT. The reaction mixture is poured into saturated NH₄Cl solution and theprecipitate formed is spin-filtered off and dried. 10.2 g of theexpected product are obtained and are used without further purificationin the following step.

[0259] C)3,5-Dichloro-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0260] 0.8 ml of pyridine is added, at RT, to a mixture of 2 g of thecompound obtained in step B in 50 ml of DCM, followed by addition of 1.2ml of thionyl chloride, and the mixture is left stirring untildissolved. The reaction mixture is washed with 1N HCl solution and thentwice with water and dried over Na₂SO₄, and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica gel, elutingwith a DCM/EtOAc mixture (95/5; v/v). 1.2 g of the expected product areobtained and are used without further purification.

[0261] Preparation 1.6

[0262] 3,5-Dichloro-3-(2,4-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0263] (IV): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=4-OCH₃; Hal=Cl

[0264] A)5-Chloro-3-hydroxy-3-(2,4-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0265] A solution of 2,4-dimethoxyphenylmagnesium bromide is preparedstarting with 2.2 g of magnesium in 10 ml of THF and a solution of 18 gof 1-bromo-2,4-dimethoxybenzene in 40 ml of THF. This solution is addeddropwise to a mixture of 5 g of 5-chloro-1H-indole-2,3-dione in 50 ml ofTHF at a temperature of 30° C., followed by refluxing for 2 hours. Thereaction mixture is cooled to RT, poured into saturated NH₄Cl solutionand extracted with EtOAc, the organic phase is washed with water anddried over Na₂SO₄, and the solvent is evaporated off under vacuum. 7.2 gof the expected product are obtained after crystallization from hot isoether.

[0266] B)3,5-Dichloro-3-(2,4-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0267] A mixture of 1.5 g of the compound obtained in the preceding stepand 0.4 ml of pyridine in 20 ml of DCM is cooled to a temperature below10° C., 0.45 ml of thionyl chloride is added dropwise and the mixture isleft stirring for 15 minutes. The reaction mixture is washed twice withwater and dried over Na₂SO₄, and this solution is used without furtherpurification in Preparations 3.13 and 3.14.

[0268] Preparation 1.7

[0269] 3,5-Dichloro-3-(2,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0270] (IV): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=5-OCH₃; Hal=Cl.

[0271] A)5-Chloro-3-hydroxy-3-(2,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0272] A solution of 2,5-dimethoxyphenylmagnesium bromide is preparedstarting with 2.2 g of magnesium, 18 g of 1-bromo-2,5-dimethoxybenzeneand 50 ml of ether. This solution is added dropwise to a mixture of 5 gof 5-chloro-1H-indole-2,3-dione in 50 ml of THF at a temperature below30° C., and is then refluxed for 3 hours. After cooling to RT, thereaction mixture is poured into 1N HCl solution and extracted withEtOAc, the organic phase is washed with water and dried over Na₂SO₄, andthe solvent is evaporated off under vacuum. 7.1 g of the expectedproduct are obtained after crystallization from hot iso ether.

[0273] B)3,5-Dichloro-3-(2,5-diemthoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0274] A mixture of 3 g of the compound obtained in the preceding stepand 1.2 ml of pyridine in 50 ml of DCM is cooled to a temperature below20° C., 0.8 ml of thionyl chloride is added and the mixture is leftstirring for 1 hour. The reaction mixture is washed with water, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica gel, eluting withDCM. 1.9 g of the expected product are obtained and are used withoutfurther purification.

[0275] Preparation 1.8

[0276] 3,5-Dichloro-3-(2,6-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0277] (IV): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=6-OCH₃; Hal=Cl

[0278] A) Ethyl 2-(2,6-dimethoxyphenyl)-2-oxoacetate

[0279] A mixture of 28 g of 1,3-dimethoxybenzene and 24.3 g of TMEDA in400 ml of hexane is cooled to a temperature below 10° C., 132 ml of a1.6 M solution of n-butyllithium in hexane are added dropwise and themixture is left stirring for 30 minutes. The reaction mixture is cooledto 0° C., 140 ml of diethyl oxalate are added over 15 minutes and themixture is left stirring for 1 hour at RT. The reaction mixture ispoured into a mixture of concentrated HCl solution and ice and isextracted with EtOAc, the organic phase is washed with water and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The excessdiethyl oxalate is removed by distillation under vacuum (b.p.=90° C. at2 400 Pa). The resulting crude product is chromatographed on silica gel,eluting with heptane and then with DCM. 34.5 g of the expected productare obtained.

[0280] B)5-Chloro-3-hydroxy-3-(2,6-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0281] A mixture of 28.5 g of tert-butyl 4-chloro-phenylcarbamate(obtained in step Ba) of Preparation 1.5) in 300 ml of ether is cooledto −40° C., 191 ml of a 1.5 M solution of tert-butyllithium in pentaneare added dropwise and the mixture is left stirring for 3 hours at −20°C. The reaction mixture is cooled to −60° C., a solution of 34.5 g ofthe compound obtained in the preceding step in 50 ml of THF is addeddropwise and the mixture is left stirring for 48 hours at RT. Thereaction mixture is poured into saturated NH₄Cl solution and extractedwith EtOAc, the organic phase is washed with water and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with DCM and then with a DCM/MeOHmixture (99/1; v/v). 8.7 g of the expected product are obtained aftercrystallization from iso ether; m.p.=182° C.

[0282] C)3,5-Dichloro-3-(2,6-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0283] 1 ml of thionyl chloride is added to a mixture of 4 g of thecompound obtained in the preceding step and 1.8 ml of pyridine in 250 mlof DCM, and the mixture is left stirring for 30 minutes at RT. Thereaction mixture is washed with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. 1.8 g of theexpected product are obtained after crystallization from iso ether.

[0284] Preparation 1.9

[0285] 3,5-Dichloro-3-(3,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0286] (IV): R₁=Cl; R₂=H; R₃=3-OCH₃; R₄=5-OCH₃; Hal=Cl

[0287] A)5-Chloro-3-hydroxy-3-(3,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0288] This compound is prepared according to the procedure described instep A of Preparation 1.6, starting with 1.2 g of magnesium, 9.5 g of1-bromo-3,5-dimethoxybenzene, 50 ml of THF and a solution of 3 g of5-chloro-1H-indole-2,3-dione in 50 ml of THF. 3.2 g of the expectedproduct are obtained after crystallization from iso ether; m.p.=191° C.

[0289] B)3,5-Dichloro-3-(3,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0290] A mixture of 3.2 g of the compound obtained in the preceding stepand 0.7 ml of pyridine in 100 ml of DCM is cooled to a temperature below20° C., 0.7 ml of thionyl chloride is added and the mixture is leftstirring for 15 minutes. The reaction mixture is washed with water, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated offunder vacuum. 1.4 g of the expected product are obtained aftercrystallization from iso ether; m.p.=157° C.

[0291] Preparation 1.10

[0292] 3,5-Dichloro-3-(1,3-benzodioxol-4-yl)-1,3-dihydro-2H-indol-2-one

[0293] (IV): R₁=Cl; R₂=H; R₃+R₄=2,3-O—CH₂O—; Hal=Cl

[0294] A) 4-Bromo-1,3-benzodioxole

[0295] This compound is prepared according to the process described inTetrahedron Lett., 1995, 36, 6413-6414.

[0296] B)5-Chloro-3-(1,3-benzodioxol-4-yl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

[0297] A solution of 1,3-benzodioxol-4-ylmagnesium bromide is preparedstarting with 0.85 g of magnesium in 10 ml of THF and a solution of 6.7g of the compound obtained in the preceding step in 40 ml of THF. Thissolution is added dropwise and at a temperature below 40° C. to amixture of 3 g of 5-chloro-1H-indole-2,3-dione in 50 ml of THF and theresulting mixture is then left stirring for one hour. The reactionmixture is poured into saturated NH₄Cl solution and extracted withEtOAc, the organic phase is washed with water and dried over Na₂SO₄, andthe solvent is evaporated off under vacuum. 1.12 g of the expectedproduct are obtained after crystallization from DCM; m.p.=271° C.

[0298] C)3,5-Dichloro-3-(1,3-benzodioxol-4-yl)-1,3-dihydro-2H-indol-2-one

[0299] 0.3 ml of thionyl chloride is added, at a temperature below 25°C., to a mixture of 1.1 g of the compound obtained in the preceding stepand 0.4 ml of pyridine in 20 ml of DCM, and the mixture is left stirringfor 30 minutes. The reaction mixture is washed twice with water, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated offunder vacuum. 0.62 g of the expected product is obtained aftercrystallization from DCM; m.p.=241° C.

[0300] Preparation 1.11

[0301]3,5-Dichloro-3-(2-trifluoromethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0302] (IV): R₁=Cl; R₂=H; R₃=2-OCF₃; R₄=H; Hal=Cl

[0303] A)5-Chloro-3-hydroxy-3-(2-trifluoromethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0304] A solution of 25 g of 1-bromo-2-trifluoromethoxybenzene in 130 mlof ether is added dropwise to a mixture of 2.8 g of magnesium in 20 mlof ether, the reflux being maintained once it has started. At the end ofthe addition, the mixture is refluxed for one hour. A mixture of 7.5 gof 5-chloro-1H-indole-2,3-dione in 100 ml of THF is then added, at atemperature below 40° C., followed by refluxing for one hour. Aftercooling to RT, the reaction mixture is poured into an ice/concentratedHCl mixture and extracted with EtOAc, the organic phase is washed withwater and with 1N NaOH solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. 6.5 g of the expected product areobtained after crystallization from a DCM/iso ether mixture (20/80;v/v); m.p.=214° C.

[0305] B)3,5-Dichloro-3-(2-trifluoromethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0306] 0.7 ml of thionyl chloride is added, at a temperature below 20°C., to a mixture of 2.7 g of the compound obtained in the preceding stepand 1 ml of pyridine in 20 ml of DCM, and the mixture is left stirringfor one hour. The reaction mixture is washed twice with water, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated offunder vacuum. 1.8 g of the expected product are obtained aftercrystallization from iso ether; m.p.=185° C.

[0307] Preparation 1.12

[0308] 3-Bromo-5-chloro-3-(2-fluorophenyl)-1,3-dihydro-2H-indol-2-one

[0309] (IV): R₁=Cl; R₂=H; R₃=2-F; R₄=H; Hal=Br

[0310] A) D,L-2-Fluoromandelic Acid

[0311] This compound is prepared according to the process described inJ. Org. Chem., 1968, 33, 2565-2566. This compound may also be preparedby following the procedure below. A mixture of 17.4 g of2-fluorobenzaldehyde and 9.6 g of potassium cyanide in 30 ml of ether iscooled to a temperature below 10° C., 15 ml of concentrated HCl areadded over 30 minutes and the mixture is left stirring for 2 hours atRT. After separation of the phases by settling, the organic phase isdried over Na₂SO₄ and the solvent is evaporated off under vacuum. Thecrude product thus obtained is taken up in 20 ml of concentrated HCl andrefluxed for 5 hours. After cooling to RT, the reaction mixture isextracted with ether, the organic phase is washed with water and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. 17.5 g ofthe expected product are obtained after crystallization from iso ether.

[0312] B) N-p-Chlorophenyl-D,L-2-fluoromandelamide

[0313] A mixture of 17.5 g of the compound obtained in the precedingstep and 13 g of p-chloroaniline in 100 ml of 1,2-dichlorobenzene isrefluxed for 3 hours, while removing the water formed using Dean-Starkapparatus. After cooling to RT, the mixture is left to crystallize. Theprecipitate formed is spin-filtered off and dissolved in EtOAc, theorganic phase is washed twice with 4N HCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. 16.2 g of theexpected product are obtained after crystallization from iso ether.

[0314] C) 5-Chloro-3-(2-fluorophenyl)-1,3-dihydroindol-2-one

[0315] 16.1 g of the compound obtained in the preceding step are addedto a mixture of 64 ml of concentrated (95%) H₂SO₄ and 16 ml of fumingsulphuric acid (30% oleum) at RT, and the mixture is then left stirringfor 8 hours. The reaction mixture is poured into a mixture of ice/waterand extracted with EtOAc, the organic phase is washed twice with waterand dried over Na₂SO₄ and the solvent is evaporated off under vacuum.12.2 g of the expected product are obtained after crystallization fromiso ether.

[0316] D) 3-Bromo-5-chloro-3-(2-fluorophenyl)-1,3-dihydro-2H-indol-2-one

[0317] A solution of 0.78 ml of bromine in 20 ml of chloroform is addedslowly at RT to a solution of 4 g of the compound obtained in thepreceding step in 100 ml of chloroform. The reaction mixture isconcentrated under vacuum to give 4 g of the expected product aftercrystallization from iso ether.

[0318] Preparation 1.13

[0319] 3,5-Dichloro-3-(2-benzyloxyphenyl)-1,3-dihydro-2H-indol-2-one

[0320] (IV): R₁=Cl; R₂=H; R₃=2-OBzl; R₄=H; Hal=Cl

[0321] A) 1-Bromo-2-benzyloxybenzene

[0322] A mixture of 35 g of 1-bromo-2-hydroxybenzene, 30.5 g of benzylchloride and 50 g of K₂CO₃ in 500 ml of acetone is refluxed for 12hours. The reaction mixture is concentrated under vacuum, the residue istaken up in a water/EtOAc mixture, the organic phase is washed with 1NNaOH solution and with water and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The resulting oil is distilled underreduced pressure to give 50.3 g of the expected product, b.p.=155° C. at40 Pa.

[0323] B)5-Chloro-3-(2-benzyloxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

[0324] A solution of 50 g of the compound obtained in the preceding stepin 80 ml of THF is added dropwise to a mixture of 5.1 g of magnesium in20 ml of THF, the reflux being maintained once it has started. At theend of the addition, the mixture is refluxed for 3 hours. This solutionis then added dropwise, at a temperature below 40° C., to a mixture of13 g of 5-chloro-1H-indole-2,3-dione in 100 ml of THF and the resultingmixture is then refluxed for 2 hours. After cooling to RT, the reactionmixture is poured into saturated NH₄Cl solution precooled on an icebath, and is extracted with EtOAc, the organic phase is washed withwater and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is taken up in iso ether and left to crystallize.The precipitate formed is spin-filtered off and washed with boiling isoether. 16.1 g of the expected product are obtained; m.p.=197° C.

[0325] C) 3,5-Dichloro-3-(2-benzyloxyphenyl)-1,3-dihydro-2H-indol-2-one

[0326] 0.4 ml of thionyl chloride is added, at a temperature below 20°C., to a solution of 1.35 g of the compound obtained in the precedingstep and 0.6 ml of pyridine in 30 ml of DCM, and the mixture is leftstirring for 30 minutes. The reaction mixture is washed with water, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated offunder vacuum. 1.18 g of the expected product are obtained aftercrystallization from iso ether.

[0327] Preparation 1.14

[0328]3,5-Dichloro-3-(2-methoxy-6-methylphenyl)-1,3-dihydro-2H-indol-2-one

[0329] (IV): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=6-CH₃; Hal=Cl

[0330] A)5-Chloro-3-hydroxy-3-(2-methoxy-6-methyl-phenyl)-1,3-dihydro-2H-indol-2-one

[0331] A solution of 2-methoxy-6-methylphenyl-magnesium bromide isprepared starting with 2.2 g of magnesium in 10 ml of THF and a solutionof 16 g of 1-bromo-2-methoxy-6-methylbenzene in 40 ml of THF. Thissolution is added dropwise at RT to a mixture of 6 g of5-chloro-1H-indole-2,3-dione in 50 ml of THF and the resulting mixtureis then refluxed for 1 hour. After cooling to RT, the reaction mixtureis poured into 200 ml of 3N HCl solution and extracted with EtOAc, theorganic phase is washed with water and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. 5.7 g of the expected productare obtained after crystallization from iso ether.

[0332] B)3,5-Dichloro-3-(2-methoxy-6-methylphenyl)-1,3-dihydro-2H-indol-2-one

[0333] A mixture of 3 g of the compound obtained in the preceding stepand 1 ml of pyridine in 20 ml of DCM is cooled to a temperature below10° C., 1.3 g of thionyl chloride are added and the mixture is leftstirring for 30 minutes at RT. The reaction mixture is washed withwater, the organic phase is dried over Na₂SO₄ and the solvent isevaporated off under vacuum. 1 g of the expected product is obtainedafter crystallization from iso ether.

[0334] Preparation 1.15

[0335]3-Chloro-3-(2-methoxyphenyl)-5-trifluoro-methoxy-1,3-dihydro-2H-indol-2-one

[0336] (IV): R₁=OCF₃; R₂=H; R₃=2-OCH₃; R₄=H; Hal=Cl

[0337] A)3-Hydroxy-3-(2-methoxyphenyl)-5-trifluoro-methoxy-1,3-dihydro-2H-indol-2-one

[0338] A solution of 2-methoxyphenylmagnesium bromide is preparedstarting with 1.9 g of magnesium in 4 ml of ether and a solution of14.54 g of 1-bromo-2-methoxybenzene in 21 ml of ether. This solution isadded dropwise, under an argon atmosphere, to a mixture of 5 g of5-trifluoromethoxy-1H-indole-2,3-dione in 26 ml of THF, precooled on anice bath, the resulting mixture is then heated at the reflux temperatureof the ether for 1 hour 30 minutes and is allowed to cool to RT. Thereaction mixture is poured slowly into saturated NH₄Cl solution andextracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, with water and with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. 2.8 g of theexpected product are obtained.

[0339] B)3-Chloro-3-(2-methoxyphenyl)-5-trifluoro-methoxy-1,3-dihydro-2H-indol-2-one

[0340] A mixture of 1 g of the compound obtained in the preceding stepin 10 ml of DCM is cooled to 0° C., 0.24 ml of pyridine and then 0.22 mlof thionyl chloride are added and the mixture is left stirring for 15minutes. This solution is used in this form in Preparation 3.30.

[0341] Preparation 1.16

[0342] 3,5,6-Trichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0343] (IV): R₁=Cl; R₂=6-Cl; R₃=2-OCH₃; R₄=H; Hal=Cl

[0344] A) 5,6-Dichloro-1H-indole-2,3-dione

[0345] This compound is prepared according to the procedure described inJ. Am. Chem. Soc., 1946, 68, 2697-2703 or according to the proceduredescribed in J. Org. Chem., 1952, 17, 149-156.

[0346] B)5,6-Dichloro-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0347] 5.57 g of 1-bromo-2-methoxybenzene are added dropwise to asuspension of 0.72 g of magnesium in 15 ml of ether containing a fewcrystals of iodine, the reflux being maintained once it has started. Atthe end of the addition, the mixture is refluxed for 2 hours. Asuspension of 2.7 g of 5,6-dichloro-1H-indole-2,3-dione in 30 ml of THFis then added and the mixture is refluxed for 30 minutes. After coolingto RT, the reaction mixture is poured into a water/ice/concentrated HClmixture and extracted with EtOAc, the organic phase is dried over Na₂SO₄and the solvent is evaporated off under vacuum. The residue is slurriedin hot iso ether and the precipitate formed is spin-filtered off andwashed with ether. 3 g of the expected product are obtained.

[0348] C) 3,5,6-Trichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0349] A suspension of 1.5 g of the compound obtained in the precedingstep in 30 ml of DCM is cooled on an ice bath and 0.56 ml of pyridine isadded, followed by 0.5 ml of thionyl chloride. After stirring for 1 hourat RT, the reaction mixture is diluted by adding DCM, the organic phaseis washed with water to neutral pH and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. 1.5 g of the expected productare obtained in the form of a foam, which is used without furtherpurification.

[0350] Preparation 1.17

[0351]3-Bromo-5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

[0352] (IV): R₁=Cl; R₂=6-Cl; R₃=2-Cl; R₄=H; Hal=Br

[0353] A) N-3,4-Dichlorophenyl-D,L-2-chloromandelamide

[0354] This compound is prepared according to the procedure described instep B of Preparation 1.12, starting with 3,4-dichloroaniline andD,L-2-chloromandelic acid; m.p.=160-163° C.

[0355] B) 5,6-Dichloro-3-(2-chlorophenyl)-1,3-dihydro-indol-2-one

[0356] A mixture of 53 ml of concentrated sulphuric acid and 12 ml offuming sulphuric acid (30% oleum) is cooled to 0° C. and 13 g of thecompound obtained in the preceding step are added portionwise. Themixture is left stirring for 24 hours at RT, the reaction mixture ispoured into water and the precipitate formed is spin-filtered off. Theprecipitate is dissolved in EtOAc, the organic phase is washed withwater to pH 7 and dried over sodium sulphate, and the solvent ispartially evaporated off under vacuum. The crystalline product formed isspin-filtered off and recrystallized from a THF/DCM/EtOAc mixture. 1.3 gof the expected product are obtained; m.p. 198-201° C.

[0357] C) 3-Bromo-5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

[0358] A solution of 0.32 g of bromine in 1 ml of chloroform is addeddropwise to a suspension of 1.95 g of the compound obtained in thepreceding step in 30 ml of chloroform, and the mixture is left stirringfor 30 minutes at RT. The reaction mixture is concentrated under vacuum,the residue is taken up in DCM and the solvent is evaporated off undervacuum. The residue is extracted with EtOAc, the organic phase is washedwith water to pH 7 and dried over sodium sulphate, and the solvent isevaporated off under vacuum. The expected product is obtained aftercrystallization from DCM; m.p.=215-218° C.

[0359] Preparation 1.18

[0360]3-Bromo-4,5-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

[0361] (IV): R₁=Cl; R₂=4-Cl; R₃=2-Cl; R₄=H; Hal=Br

[0362] A) 5,6-Dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one and4,5-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

[0363] The process is performed as in step B of Preparation 1.17,starting with 93 g of N-3,4-dichloro-phenyl-D,L-2-chloromandelamide.After spin-filtration of the precipitate formed corresponding to5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one, thespin-filtration liquor is concentrated under vacuum to give a mixture ofthe two expected products, which is used without further purification.

[0364] B)3-Bromo-4,5-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

[0365] A solution of 1.71 ml of bromine in 10 ml of DCM is addeddropwise at RT to a suspension of 11.55 g of the mixture of compoundsobtained in the preceding step in 200 ml of DCM, and, at the end of theaddition, a further 0.38 ml of bromine is added. The reaction mixture isconcentrated under vacuum, the residue is extracted with EtOAc, theorganic phase is washed with water and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a gradient of the DCM/EtOAc mixture. Thefollowing are obtained:

[0366] the compound of Preparation 1.17 eluted with a DCM/EtOAc mixture(88/12; v/v).

[0367]¹H NMR: d₆-DMSO: δ (ppm): 7.1: 2s: 2H; 7.5: up: 3H; 8.3: dd: 1H;11.5: bs: 1H.

[0368] the compound of Preparation 1.18 eluted with a DCM/EtOAc mixture(76/24; v/v).

[0369]¹H NMR: d₆-DMSO: δ (ppm): 7.2: d: 1H; 7.5: up: 4H; 8.3: dd: 1H;11.5: bs: 1H.

[0370] Preparation 1.19

[0371]3,5-Dichloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

[0372] (IV): R₁=Cl; R₂=6-CH₃; R₃=2-OCH3; R₄=H; Hal=Cl

[0373] A) Ethyl 2-(2-methoxyphenyl)-2-oxoacetate

[0374] A solution of 27 g of 1-bromo-2-methoxy-benzene in 270 ml ofether is cooled to −70° C. under an argon atmosphere, 90 ml of a 1.6 Msolution of n-butyl-lithium in pentane are added dropwise and themixture is then left stirring for 45 minutes. 78 ml of diethyl oxalateare added rapidly and the mixture is left stirring, while allowing thetemperature to return to RT. After stirring for 1 hour at RT, saturatedNH₄Cl solution is added to the mixture, the phases are separated aftersettling has taken place, the aqueous phase is extracted with ether, thecombined organic phases are washed with water and then with saturatedNaCl solution and dried over Na₂SO₄, and the solvents are evaporated offunder vacuum. The excess diethyl oxalate is removed by distillationunder vacuum (b.p.=87° C. at 2 000 Pa). The resulting product ischromatographed on silica gel, eluting with a DCM/hexane mixture (50/50;v/v) and then with DCM. The product obtained is purified by distillationunder vacuum. 13 g of the expected product are obtained; b.p.=110° C. at3 Pa.

[0375] B)5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

[0376] a) tert-Butyl 4-chloro-3-methylphenyl-carbamate

[0377] A mixture of 10 g of 4-chloro-3-methylaniline and 15.26 g ofdi-tert-butyl dicarbonate in 50 ml of dioxane is left stirring for 24hours at RT. The reaction mixture is concentrated under vacuum and theresidue is chromatographed on silica gel, eluting with a gradient of aDCM/hexane mixture of from (50/50; v/v) to (70/30; v/v). 5.6 g of theexpected product are obtained and are used without further purification.

[0378] b) A solution of 5 g of tert-butyl4-chloro-3-methylphenylcarbamate in 45 ml of ether is cooled to −70° C.under an argon atmosphere, 30 ml of a 1.5M solution of tert-butyllithiumin pentane are added dropwise, the mixture is left stirring for 1 hourwhile allowing the temperature to rise to −10° C., and is left stirringfor 1 hour 45 minutes at −10° C. The reaction mixture is cooled to −70°C., a solution of 5 g of the compound obtained in step A in 25 ml of THFis added dropwise and the mixture is left stirring for 1 hour whileallowing the temperature to rise to −30° C., and is then stirredovernight while allowing the temperature to rise to RT. Saturated NH₄Clsolution is added to the reaction mixture, the THF is evaporated off,the resulting aqueous phase is extracted three times with EtOAc, theorganic phase is washed with water, with saturated NaCl solution anddried over Na₂SO₄, the solvent is partially evaporated off and thecrystalline product is spin-filtered off. 2.6 g of the expected productare obtained; m.p.=254-256° C.

[0379] C)3,5-Dichloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

[0380] A mixture of 2.0 g of the compound obtained in step B in 45 ml ofDCM is cooled to 0° C., 0.77 ml of pyridine and then 1.17 g of thionylchloride are added and the mixture is left stirring for 2 hours afterthe temperature has been allowed to return to RT. Water and DCM areadded to the reaction mixture and, after separation of the phases bysettling, the organic phase is washed four times with water and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. Theexpected product is obtained and is used without further purification.

[0381] Preparation 1.20

[0382]3,5-Dichloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one

[0383] (IV): R₁=Cl; R₂=6-OCH₃; R₃=2-Cl; R₄=H; Hal=Cl

[0384] A) 4-Chloro-3-methoxyaniline

[0385] A mixture of 36 g of 2-chloro-5-nitroanisole and Raney nickel® in150 ml of MeOH and 200 ml of THF is hydrogenated in Parr apparatus for 4hours, at 35° C. and under a pressure of 1.3 bar. The catalyst isfiltered off over Celite® and the filtrate is concentrated under vacuum.28 g of the expected product are obtained and are used without furtherpurification.

[0386] B) N-(4-Chloro-3-methoxyphenyl)-D,L-2-chloro-mandelamide

[0387] A mixture of 28 g of the compound obtained in the preceding stepand 33.13 g of D,L-2-chloromandelic acid in 128 ml of1,2-dichlorobenzene is heated at 230° C. for 4 hours, while removing thewater formed using Dean-Stark apparatus. The reaction mixture ispartially concentrated under vacuum and is left to crystallize. Thecrystalline product formed is spin-filtered off and washed with isoether. 40 g of the expected product are obtained.

[0388] C)5-Chloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one

[0389] 40 g of the compound obtained in the preceding step are addedrapidly to 550 g of polyphosphoric acid and the mixture is then heatedat 60° C. for 8 hours and left stirring overnight while allowing thetemperature to return to RT. Ice-cold water is added to the reactionmixture and the precipitate formed is spin-filtered off and washed withwater. The precipitate is taken up in EtOAc and the white productobtained after slurrying is spin-filtered off and washed with iso ether.17.2 g of the expected product are obtained; m.p.=243-247° C.

[0390] D)5-Chloro-3-(2-chlorophenyl)-3-hydroxy-6-methoxy-1,3-dihydro-2H-indol-2-one

[0391] 2.56 g of 60% sodium hydride in oil are added at RT, under anargon atmosphere, to a solution of 17.2 g of the compound obtained inthe preceding step in 220 ml of THF. After the evolution of gas hasceased, 6.85 g of dimethyl disulphide are added, air is bubbled into thereaction mixture and this mixture is left stirring for 72 hours at RT.Water is added to the reaction mixture, the THF is evaporated off undervacuum, the remaining aqueous phase is extracted with EtOAc, the organicphase is washed with water and with saturated NaCl solution and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The productobtained is dissolved in DCM, the solvent is partially concentrated, themixture is left to crystallize and the crystalline product formed isspin-filtered off. 6 g of the expected product are obtained;

[0392] m.p.=237-240° C.

[0393] E)3,5-Dichloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one

[0394] A suspension of 2.0 g of the compound obtained in the precedingstep in 30 ml of DCM is cooled on an ice bath, 0.5 ml of pyridine andthen 0.44 ml of thionyl chloride are added and this mixture is leftstirring for 30 minutes. At the end of the reaction, a solution of theexpected product is obtained, and this solution is used directly inPreparations 3.37 and 3.38.

[0395] Preparation 1.21

[0396]3,5-Dichloro-3-(2-chlorophenyl)-4-methoxy-1,3-dihydro-2H-indol-2-one

[0397] (IV): R₁=Cl; R₂=4-OCH₃; R₃=2-Cl; R₄=H; Hal=Cl

[0398] A)5-Chloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one and5-chloro-3-(2-chlorophenyl)-4-methoxy-1,3-dihydro-2H-indol-2-one

[0399] The process is performed as in step C of Preparation 1.20. Afterspin-filtration of the precipitate formed corresponding to5-chloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one, thespin-filtration liquor is concentrated under vacuum to give a mixture ofthe two expected products, which is used without further purification.

[0400] B)5-Chloro-3-(2-chlorophenyl)-3-hydroxy-4-methoxy-1,3-dihydro-2H-indol-2-one

[0401] 1.14 g of 60% sodium hydride in oil are added at RT to a solutionof 8 g of the mixture of compounds obtained in the preceding step in 100ml of THF. After the evolution of gas has ceased, 3 ml of dimethyldisulphide are added, air is bubbled into the reaction mixture and thismixture is left stirring for 72 hours at RT. Water is added to thereaction mixture, the solvents are concentrated under vacuum, theresidue is extracted with EtOAc, the organic phase is washed with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. 3.05 g of the expected product areobtained after crystallization from DCM; m.p.=228-229° C.

[0402] C)3,5-Dichloro-3-(2-chlorophenyl)-4-methoxy-1,3-dihydro-2H-indol-2-one

[0403] A suspension of 1.5 g of the compound obtained in the precedingstep in 20 ml of DCM is cooled on an ice bath, 0.37 ml of pyridine andthen 0.34 ml of thionyl chloride are added and the mixture is leftstirring for 15 minutes. At the end of the reaction, a solution of theexpected product in DCM is obtained and is used in this form inPreparations 3.39 and 3.40.

[0404] Preparation 1.22

[0405]3-Bromo-5-chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-2H-indol-2-one

[0406] (IV): R₁=Cl; R₂=7-F; R₃=2-Cl; R₄=H; Hal=Br

[0407] This compound is prepared according to the procedures disclosedin WO 95/18105 in steps A, B and C of Preparation 73.

[0408] Preparation 1.23

[0409]3,6-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

[0410] (IV): R₁=CH₃; R₂=6-Cl; R₃=2-OCH₃; R₄=H; Hal=Cl

[0411] A) 6-Chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one

[0412] 8.5 ml of chlorine are introduced into 320 ml of DCM cooled to−70° C., followed by addition, over 20 minutes and at −70° C., of asolution of 24 ml of ethyl methylthioacetate in 60 ml of DCM, and themixture is left stirring for 15 minutes at −70° C. A solution of 52.64 gof 3-chloro-4-methylaniline in 100 ml of DCM is then added, at −70° C.and over 30 minutes, and the resulting mixture is left stirring for 1hour 45 minutes at −70° C. Finally, 41.3 ml of triethylamine are addedat −70° C. and the mixture is left stirring for 1 hour while allowingthe temperature to rise to RT. The reaction mixture is washed twice with250 ml of water, the organic phase is dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is taken up in a mixture of600 ml of ether and 130 ml of 2N HCl and is left stirring for 72 hoursat RT. An insoluble material is filtered off, the filtrate is allowed toseparate by settling, the organic phase is washed twice with water anddried over MgSO₄, and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with DCM and then witha DCM/EtOAc mixture (85/15; v/v). The mixture obtained isre-chromatographed on silica gel, eluting with DCM and then with aDCM/EtOAc mixture (95/5; v/v). The two isomers are separated:

[0413] the less polar isomer, which is6-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one, in a yield of1.16 g;

[0414] the more polar isomer, which is4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one, in a yield of0.72 g.

[0415] B) 6-Chloro-5-methyl-1H-indole-2,3-dione

[0416] A mixture of 1.16 g of6-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one obtained inthe preceding step and 0.681 g of N-chlorosuccinimide in 100 ml ofcarbon tetrachloride is refluxed for 1 hour. The reaction mixture isconcentrated under vacuum, the residue is taken up in a mixture of 80 mlof THF and 20 ml of water, and this mixture is then refluxed for 16hours. The THF is evaporated off under vacuum, the remaining aqueousphase is extracted with EtOAc, the organic phase is washed with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM and then with a gradient of a DCM/EtOAc mixture upto (85/15; v/v). 0.793 g of the expected product is obtained; m.p.=264°C.

[0417] C)6-Chloro-3-hydroxy-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

[0418] A solution of 2-methoxyphenylmagnesium bromide is preparedstarting with 0.687 g of magnesium in 1.5 ml of ether and a solution of5.35 g of 1-bromo-2-methoxybenzene in 7.55 ml of ether. This solution isadded dropwise, under an argon atmosphere, to a mixture of 1.4 g of thecompound obtained in the preceding step in 14 ml of THF precooled on anice bath, and the resulting mixture is then left stirring while allowingthe temperature to rise to RT. After stirring for 1 hour at RT, thereaction mixture is poured slowly into saturated NH₄Cl solution, the THFis evaporated off under vacuum, the residue is extracted with EtOAc, theorganic phase is washed with water and with saturated NaCl solution anddried over Na₂SO₄, and the EtOAc is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with DCM and then witha DCM/MeOH mixture (98/2; v.v). 1.6 g of the expected product areobtained after crystallization from a THF/MeOH mixture; m.p.=266° C.

[0419] D)3,6-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

[0420] A suspension of 0.913 g of the compound obtained in the precedingstep in 10 ml of DCM is cooled on an ice bath, 0.36 ml of pyridine andthen 0.33 ml of thionyl chloride are added and the mixture is leftstirring for 20 minutes. The reaction mixture is diluted by adding 50 mlof DCM, the organic phase is washed three times with water and driedover Na₂SO₄ and is partially concentrated under vacuum to a volume of 5ml. This solution of the expected product is used in this form inPreparations 3.43 and 3.44.

[0421] Preparation 1.24

[0422]3,4-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

[0423] (IV): R₁=CH₃; R₂=4-Cl; R₃=2-OCH₃; R₄=H; Hal=Cl

[0424] A) 4-Chloro-5-methyl-1H-indole-2,3-dione

[0425] This compound is prepared according to the procedure described instep B of Preparation 1.23, starting with 0.72 g of4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and 0.422 g ofN-chloro-succinimide in 72 ml of carbon tetrachloride, and then 58 ml ofTHF and 14 ml of water. The product obtained is chromatographed onsilica gel, eluting with DCM and then with a gradient of a DCM/EtOAcmixture up to (90/10; v/v). 0.5 g of the expected product is obtained.

[0426] B)4-Chloro-3-hydroxy-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

[0427] A solution of 5 g of 1-bromo-2-methoxybenzene in 7 ml of ether isadded dropwise to a suspension of 0.638 g of magnesium in 1.5 ml ofether until the reaction starts, and the addition is then continuedwhile maintaining the reflux. At the end of the addition, the mixture isheated at 30° C. for 20 minutes. This solution is added dropwise, underan argon atmosphere, to a suspension of 1.3 g of the compound obtainedin the preceding step in 13 ml of THF precooled on an ice bath, and themixture is then left stirring while allowing the temperature to rise toRT. After 1 hour at RT, the reaction mixture is poured into saturatedNH₄Cl solution, the THF is evaporated off under vacuum, the residue isextracted with EtOAc, the organic phase is washed with water and withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM and then with a DCM/MeOH mixture (98/2; v/v).0.846 g of the expected product is obtained after crystallization from aTHF/MeOH mixture; m.p.=262-263° C.

[0428] C)3,4-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

[0429] A suspension of 0.8 g of the compound obtained in the precedingstep in 15 ml of DCM is cooled to 0° C., 0.32 ml of pyridine and then0.295 ml of thionyl chloride are added and the mixture is left stirringfor 45 minutes. The reaction mixture is diluted by adding 15 ml of DCM,the organic phase is washed three times with water and dried over MgSO₄,and the solvent is evaporated off under vacuum. 0.51 g of the expectedproduct is obtained.

[0430] Preparation 1.25

[0431]3-Chloro-3-(2-methoxyphenyl)-3,5,6,7-tetra-hydrocyclopenta[f]indol-2(1H)-one

[0432] (IV): R₁+R₂=5,6-CH₂CH₂CH₂—; R₃=2-OCH₃; R₄=H; Hal=Cl

[0433] A) N-(2,3-Dihydro-1H-inden-5-yl)-2-(hydroxyimino)acetamide

[0434] This compound is prepared according to the process described inOrganic Syntheses, 1925, V, 71-74. A solution of 16.5 ml of concentratedHCl in 120 ml of water and a solution of 41.5 g of hydroxylaminehydrochloride in 70 ml of water are added to a mixture of 25 g of5-aminoindane, 35 g of chloral hydrate and 22 g of Na₂SO₄ in 600 ml ofwater, and the mixture is then refluxed for 30 minutes. After coolingthe reaction mixture to RT, it is extracted with EtOAc, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. The residue is taken up in a pentane/iso ether mixture and theprecipitate formed is spin-filtered off. 23 g of the expected productare obtained.

[0435] B) 1,5,6,7-Tetrahydrocyclopenta[f]indole-2,3-dione

[0436] This compound is prepared according to the process described inOrganic Syntheses, 1925, V, 71-74. 23 g of the compound obtained in thepreceding step are added portionwise to 250 ml of concentrated sulphuricacid, the temperature of the reaction mixture rising to 60° C. At theend of the addition, the mixture is heated at 90° C. for 50 minutes.After cooling to RT, the reaction mixture is poured into 1 litre of ice,500 ml of EtOAc are added and the mixture is filtered through Celite®.After separation of the filtrate by settling, the organic phase is driedover Na₂SO₄ and the solvent is evaporated off under vacuum. The residueis taken up in iso ether and the crystalline product formed isspin-filtered off. 4.2 g of the expected product are obtained.

[0437] C)3-Hydroxy-3-(2-methoxyphenyl)-3,5,6,7-tetra-hydrocyclopenta[f]indol-2(1H)-one

[0438] A solution of 2-methoxyphenylmangesium bromide is preparedstarting with 2.4 g of magnesium, 16.5 g of 1-bromo-2-methoxybenzene and50 ml of ether. This solution is added dropwise, at a temperature below30° C., to a mixture of 6.3 g of the compound obtained in the precedingstep in 50 ml of THF, and the resulting mixture is then refluxed for 2hours. After cooling to RT, the reaction mixture is poured into a 3NHCl/ice mixture and extracted with EtOAc, the organic phase is washedwith water and dried over Na₂SO₄, and the solvent is evaporated offunder vacuum. The residue is taken up in hot iso ether and theprecipitate formed is spin-filtered off and washed with boiling isoether. 3.5 g of the expected product are obtained.

[0439] D)3-Chloro-3-(2-methoxyphenyl)-3,5,6,7-tetra-hydrocyclopenta[f]indol-2(1H)-one

[0440] A mixture of 3.5 g of the compound obtained in the preceding stepand 1 ml of triethylamine in 20 ml of DCM is cooled to 10° C., 0.8 ml ofthionyl chloride is added and the mixture is left stirring for 15minutes. The reaction mixture is washed with water and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The expectedproduct is obtained and is used without further purification.

[0441] Preparation 1.26

[0442]3-Chloro-3-(2-methoxy-6-methylphenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

[0443] (IV): R₁=CH₃; R₂=6-CH₃; R₃=2-OCH₃; R₄=6-CH₃; Hal=Cl

[0444] A) 5,6-Dimethyl-1H-indol-2,3-dione

[0445] This compound is prepared according to the procedures describedin steps A and B of Preparation 1.25, starting with 3,4-dimethylaniline.

[0446] B)3-Hydroxy-3-(2-methoxy-6-methylphenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

[0447] A solution of 2-methoxy-6-methylphenyl-magnesium bromide isprepared starting with 13.75 g of 1-bromo-2-methoxy-6-methylbenzene, 1.9g of magnesium and 30 ml of THF. This solution is added dropwise at RTto a suspension of 5 g of the compound obtained in the preceding step in40 ml of THF, and the resulting mixture is then refluxed for 1 hour 30minutes. After cooling to RT, 200 ml of 3N HCl solution are added, themixture is extracted with EtOAc, the organic phase is washed with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/EtOAc/THF mixture (70/20/10; v/v/v). 3 g of theexpected product are obtained after crystallization; m.p.=288° C.

[0448] C)3-Chloro-3-(2-methoxy-6-methylphenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

[0449] A mixture of 1.5 g of the compound obtained in the preceding stepin 20 ml of DCM is cooled on an ice bath, 0.4 ml of pyridine and then0.5 ml of thionyl chloride are added and the mixture is left stirringfor 15 minutes under cold conditions and then for 15 minutes at RT. Asuspension of the expected product in DCM is obtained and is used inthis form in Preparation 3.47.

[0450] Preparation 1.27

[0451]3,5-Dichloro-3-(2-methoxyphenyl)-6-trifluoro-methyl-1,3-dihydro-2H-indol-2-one

[0452] (IV): R₁=Cl; R₂=6-CF₃; R₃=2-OCH₃; R₄=H; Hal=Cl

[0453] A)5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one

[0454] a) tert-Butyl 4-chloro-3-trifluoromethyl-phenylcarbamate

[0455] This compound is prepared according to the procedure described instep B a) of Preparation 1.5, starting with4-chloro-3-trifluoromethylaniline and di-tert-butyl dicarbonate indioxane. The expected product is obtained in the form of an oil whichsolidifies; m.p.=90° C.

[0456] b) A solution of 4 g of tert-butyl4-chloro-3-trifluoromethylphenylcarbamate in 30 ml of ether is cooled to−70° C., under an argon atmosphere, 22 ml of a 1.5 M solution oftert-butyllithium in pentane are added dropwise and the mixture is leftstirring for 1 hour while allowing the temperature to rise to −10° C.and is left stirring for 2 hours 30 minutes at −10° C. The reactionmixture is cooled to −70° C., a solution of 3.05 g of the compoundobtained in step A of Preparation 1.19 in 15 ml of THF is added dropwiseand the resulting mixture is left stirring for 1 hour while allowing thetemperature to rise to −30° C., and is then stirred for 16 hours whileallowing the temperature to rise to RT. Saturated NH₄Cl solution isadded to the reaction mixture, the ether and THF are evaporated off, theresulting aqueous phase is extracted with EtOAc, the organic phase iswashed with water and with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with DCM and then with aDCM/EtOAc mixture (90/10; v/v). 1.48 g of the expected product areobtained after crystallization from an iso ether/hexane mixture; m.p.230-231° C.

[0457] B)3,5-Dichloro-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one

[0458] A suspension of 1.3 g of the compound obtained in step A in 8 mlof DCM is cooled to 0° C., 0.43 ml of pyridine and then 0.4 ml ofthionyl chloride are added and the mixture is left stirring for 15minutes. The reaction mixture is washed three times with water, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated offunder vacuum. 1.2 g of the expected product are obtained and are usedwithout further purification.

[0459] Preparation 1.28

[0460]3-Chloro-3-(2-chlorophenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

[0461] (IV): R₁=CH₃; R₂=6-CH₃; R₃=Cl; R₄=H; Hal=Cl

[0462] A) N-(3,4-Dimethylphenyl)-D,L-2-chloromandelamide

[0463] A mixture of 50 g of 3,4-dimethylaniline and 76.5 g ofD,L-2-chloromandelic acid in 250 ml of 1,2-dichlorobenzene is heated at227° C. for 7 hours, while removing the water formed using Dean-Starkapparatus. The reaction mixture is concentrated to half its volume undervacuum and is left to crystallize at RT. The crystalline product formedis spin-filtered off and washed with iso ether. 89.42 g of the expectedproduct are obtained, a sample of which is recrystallized from a DCM/isoether mixture; m.p.=172-173° C.

[0464] B) 3-(2-Chlorophenyl)-5,6-dimethyl-1,3-dihydro-indol-2-one

[0465] 100 ml of 95% sulphuric acid are cooled to −10° C., 12 ml offuming sulphuric acid (65% oleum) are added dropwise over 30 minutes andthe mixture is left stirring while allowing the temperature to rise to+10° C. The mixture is cooled again to 0° C., 23.8 g of the compoundobtained in the preceding step are added portionwise over 10 minutes andthe mixture is left stirring while allowing the temperature to rise,which stabilizes at 29° C. After stirring for 2 hours at RT, thereaction mixture is poured onto ice and the precipitate formed isspin-filtered off. The precipitate is dissolved in 1 000 ml of DCM and200 ml of THF, the pH is brought to 2 by adding solid K₂CO₃, theresulting mixture is filtered and the filtrate is concentrated undervacuum. The residue is chromatographed on silica gel, eluting with agradient of a DCM/EtOAc/THF mixture of from (90/10/5; v/v/v) to 80/20/5;v/v/v). 7.72 g of the expected product are obtained; m.p.=231° C.

[0466] C)3-(2-Chlorophenyl)-3-hydroxy-5,6-dimethyl-1,3-dihydroindol-2-one

[0467] 0.65 g of 60% sodium hydride in oil is added at RT, under anargon atmosphere, to a solution of 4 g of the compound obtained in thepreceding step in 70 ml of THF. After the evolution of gas has ceased,1.7 ml of dimethyl disulphide are then added and a stream of air isbubbled into the reaction mixture for 4 hours at RT. The reactionmixture is poured into water, the THF is concentrated under vacuum, theaqueous phase is extracted with EtOAc, the organic phase is washed withwater and with saturated NaCl solution and dried over Na₂SO₄, thesolvent is partially concentrated under vacuum and the crystallineproduct formed is spin-filtered off. 3.3 g of the expected product isobtained; m.p.=251-253° C.

[0468] D)3-Chloro-3-(2-chlorophenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

[0469] A suspension of 2 g of the compound obtained in the precedingstep in 15 ml of DCM is cooled to 0° C., 0.8 ml of pyridine and then0.74 ml of thionyl chloride are added and the mixture is left stirringfor 30 minutes. The reaction mixture is diluted by adding 60 ml of DCM,the organic phase is washed with 45 ml of water and dried over Na₂SO₄,and the solvent is partially concentrated under vacuum at a temperaturebelow 40° C., to a volume of 20 ml. This solution is used in this formin Preparations 3.60 and 3.61.

[0470] Preparation of the Compounds of Formula (V)

[0471] Preparation 2.1

[0472] (2S)-N,N-Dimethylpyrrolidine-2-carbothioamide trifluoroacetate

[0473] (V), TFA: R₅=N(CH₃)₂; W=S; n=1

[0474] A)(2S)-N,N-Dimethyl-1-(tert-butoxycarbonyl)-pyrrolidine-2-carbothioamide

[0475] This compound is prepared according to the procedure described instep A) of Example 84 of EP 0 526 348 B.

[0476] B) (2S)-N,N-Dimethylpyrrolidine-2-carbothioamide trifluoroacetate

[0477] A solution of 18 g of the compound obtained in the preceding stepin 5 ml of DCM is cooled to 4° C., 15 ml of TFA are added and themixture is left stirring for 15 hours at 4° C. The reaction mixture isconcentrated under vacuum under cold conditions, the residue is taken upfour times in DCM and the solvent is evaporated off under vacuum eachtime. 12 g of the expected product are obtained after drying, and areused without further purification.

[0478] Preparation 2.2

[0479] (2S)-N,N-Dimethylpiperidine-2-carboxamide Hydrochloride

[0480] (V), HCl: R₅=N(CH₃)₂; W=O; n=2

[0481] A)(2S)-N,N-Dimethyl-2-(tert-butoxycarbonyl)-piperidine-2-carboxamide

[0482] 6.2 g of HOBT and then 9.45 g of DCC are added at RT to asolution of 10 g of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid (commercial) in 130 ml of DCM, and the mixture is left stirring for1 hour. The reaction mixture is cooled on an ice bath, dimethylamine gasis added by bubbling for two times 10 minutes and the mixture is thenleft stirring overnight at RT. An insoluble material is filtered off andthe filtrate is concentrated under vacuum. The residue ischromatographed on silica gel, eluting with a gradient of a DCM/MeOHmixture of from (98/2; v/v) to (96/4; v/v). The product obtained istaken up in ether and the precipitate is spin-filtered off. 8.5 g of theexpected product are obtained.

[0483] B) (2S)-N,N-Dimethylpiperidine-2-carboxamide Hydrochloride

[0484] A mixture of 8.5 g of the compound obtained in the preceding stepand 85 ml of 4N hydrochloric ether is left stirring for 1 hour 30minutes. The reaction mixture is concentrated under vacuum, the residueis taken up several times with DCM and the solvent is evaporated offeach time under vacuum. 6.25 g of the expected product are obtained.

[0485] Preparation 2.3

[0486] N,N-Dimethylpiperidine-2-carboxamide Hydrochloride

[0487] (V), HCl: R₅=N(CH₃)₂; W=O; n=2

[0488] This compound is prepared according to the procedures describedin steps A and B of Preparation 2.2, starting with racemic1-(tert-butoxycarbonyl)-piperidine-2-carboxylic acid (commercial).

[0489] Preparation of the compounds of formulae (II) and (II′)

[0490] Preparation 3.1

[0491](2S)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer

[0492] (II): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=H; R₅=-N(CH₃)₂; n=1; W=O

[0493] 4.1 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide (commercial)are added to a suspension of 8.8 g of the compound obtained inPreparation 1.1 in 120 ml of chloroform and 30 ml of THF, and themixture is left stirring for 30 minutes at RT. 3.7 g of DIPEA are thenadded and the mixture is left stirring for 3 hours at RT. 0.4 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide is then added and the mixtureis left stirring for 48 hours. The reaction mixture is concentratedunder vacuum at RT, the residue is taken up in water, 300 ml of EtOAcare added, the mixture is left stirring and the precipitate present (themost polar compound on TLC on alumina DCM/MeOH (96/4; v/v)) isspin-filtered off. The precipitate is taken up in 100 ml of EtOAc, leftstirring for 2 hours and spin-filtered off. It is taken up in 100 ml ofboiling EtOAc, left stirring for 1 hour and spin-filtered off. Theprecipitate is dissolved in a hot mixture of 100 ml of THF, 50 ml ofMeOH and 10 ml of water, the resulting solution is filtered and thefiltrate is concentrated under vacuum to a volume of 100 ml and is leftovernight. 3.78 g of the expected product are obtained after thecrystalline compound formed has been spin-filtered off.α_(D)²⁵ = −242^(^(∘))(c = 0.12; chloroform)

[0494] Preparation 3.2

[0495] tert-Butyl(2S)-1-[5-chloro-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylate,laevorotatory isomer

[0496] (II′): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=H; n=1

[0497] A solution of 3.4 g of tert-butyl (2S)-pyrrolidine-2-carboxylate(commercial) in 5 ml of DCM is added to a suspension of 6 g of thecompound obtained in Preparation 1.1 in 40 ml of DCM and 20 ml of THF,followed by addition of 5.42 ml of triethylamine, and the mixture isleft stirring for 2 hours at RT. The reaction mixture is concentratedunder vacuum, the residue is extracted with EtOAc, the organic phase iswashed with 5% K₂CO₃ solution, with water and with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with DCMand then with a DCM/MeOH mixture (98/2 v/v). The diastereoisomers areseparated and the most polar compound is collected. 3.3 g of theexpected product are obtained.α_(D)²⁵ = −148.5^(^(∘))(c = 0.229; chloroform)

[0498] Preparation 3.3

[0499](2S)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-2-yl]-N,N-dimethylpyrrolidine-2-carbothioamide,laevorotatory isomer

[0500] (II): R₁=Cl; R₂=H; R₃=2-OCH3; R₄=H; R₅=N(CH₃)₂; n=1; W=S

[0501] A solution of 3.5 g of the compound obtained in Preparation 2.1and 3.5 g of triethylamine in 20 ml of DCM is added dropwise at RT to amixture of 4 g of the compound obtained in Preparation 1.1 in 20 ml ofDCM, and the mixture is left stirring for 30 minutes at RT. A further0.87 g of triethylamine is added and the mixture is left stirring for 24hours at RT. The resulting mixture is concentrated under vacuum, theresidue is extracted with EtOAc, the organic phase is washed with 5%KHSO₄ solution and with water and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on alumina,eluting with a DCM/MeOH mixture (99.75/0.25; v/v). The diastereoisomersare separated to give 0.7 g of the expected product aftercrystallization from a DCM/iso ether mixture; m.p.=225° C.α_(D)²⁵ = −236^(^(∘))(c = 0.2; chloroform)

[0502] Preparation 3.4

[0503] Methyl(2S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylate;the more polar isomer.

[0504] (II): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=H; R₅=OCH₃; n=1; W=O.

[0505] A solution of 1.7 g of methyl (2S)-pyrrolidine-2-carboxylatehydrochloride (commercial) and 1.73 ml of DIPEA in 50 ml of DCM is addedat RT to a suspension of 3 g of the compound obtained in Preparation 1.1in 20 ml of THF, and the mixture is heated at 65° C. overnight. Thereaction mixture is concentrated under vacuum, the residue is taken upin 5% K₂CO₃ solution and extracted with EtOAc, the organic phase iswashed with saturated NaCl solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/EtOAc mixture (95/5; v/v). Thediastereoisomers are separated and the fractions enriched in the morepolar compound are collected. 0.793 g of the expected product isobtained and is used without further purification.

[0506] Preparations 3.5 and 3.6

[0507](2S)-1-[5-Chloro-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,isomer A and isomer B

[0508] (II): R₁=Cl; R₂=H; R₃=2-OCH₂CH₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0509] A mixture of 2.5 g of the compound obtained in Preparation 1.2,1.2 [lacuna] of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml oftriethylamine in 20 ml of DCM is left stirring for 3 hours. The reactionmixture is washed twice with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue istaken up in DCM under cold conditions over 16 hours and the precipitateformed is spin-filtered off and washed with acetone to give 0.35 g ofthe less polar isomer, isomer A: compound of Preparation 3.5. Thespin-filtration and washing liquors are chromatographed on alumina,eluting with a DCM/MeOH mixture (98/2; v/v). The other isomer isseparated out:

[0510] the more polar isomer, isomer B: compound of Preparation 3.6, togive 0.52 g.

[0511] Preparations 3.7 and 3.8

[0512](2S)-1-[5-Chloro-3-(3-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,isomer A and isomer B

[0513] (II): R₁=Cl; R₂=H; R₃=3-OCH3; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0514] A mixture of 1 g of the compound obtained in Preparation 1.3, 0.7g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml oftriethylamine in 20 ml of DCM is left stirring for 2 hours at RT. Thereaction mixture is washed with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue istaken up in DCM, cooled to 4° C. and left for 16 hours. The precipitateformed is spin-filtered off and dried to give 0.72 g of the more polarisomer, isomer B: compound of Preparation 3.8. The spin-filtrationliquor is chromatographed on alumina, eluting with a DCM/MeOH mixture(99.9/0.1; v/v). The other isomer is separated out:

[0515] the less polar isomer, isomer A: compound of Preparation 3.7, togive 0.18 g.

[0516] Preparations 3.9 and 3.10

[0517](2S)-1-[5-Chloro-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,isomer A and isomer B

[0518] (II): R₁=Cl; R₂=H; R₃=4-OCH₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0519] 1.1 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide are added atRT to the solution of the compound obtained in Preparation 1.4 in DCM,the mixture is left stirring for 15 minutes at RT, 1.2 g oftriethylamine is then added and this mixture is left stirring for 30minutes at RT. The reaction mixture is washed with water, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. The residue is taken up in cold acetone and the crystallineproduct formed is spin-filtered off to give 0.75 g of the more polarisomer, isomer B: compound of Preparation 3.10. The spin-filtrationliquor is chromatographed on silica gel, eluting with a DCM/EtOAcmixture (95/5; v/v). The other isomer is separated out:

[0520] the less polar isomer, isomer A: compound of preparation 3.9, togive 0.37 g.

[0521] Preparations 3.11 and 3.12

[0522](2S)-1-[5-Chloro-3-(2,3-diemthoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0523] (II): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=3-OCH₃; R₅=N(CH₃)₂; n=1; W=O

[0524] A mixture of 1 g of the compound obtained in Preparation 1.5, 0.5g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 0.3 g oftriethylamine in 5 ml of DCM and 15 ml of THF is left stirring for 16hours at RT. The precipitate formed is spin-filtered off, washed withTHF and dried to give 0.22 g of the less polar isomer, isomer A:compound of Preparation 3.11. The spin-filtration and washing liquorsare concentrated under vacuum and the residue is chromatographed onsilica gel, eluting with a DCM/MeOH mixture (98.5/1.5; v/v). The otherisomer is separated out:

[0525] the more polar isomer, isomer B: compound of Preparation 3.12, togive 0.68 g.

[0526] Preparations 3.13 and 3.14

[0527](2S)-1-[5-Chloro-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0528] (II): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=4-OCH₃; R₅=N(CH₃)₂; n=1; W=O

[0529] 0.7 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 0.8 ml oftriethylamine are added at RT to the solution of the compound obtainedin Preparation 1.6 in DCM, and the mixture is left stirring for 1 hourat RT. The reaction mixture is washed twice with water, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on alumina, eluting with aDCM/MeOH mixture (99.9/01.; v/v). The diasteroisomers are separated:

[0530] the less polar, isomer A: compound of Preparation 3.13, to give0.13 g.

[0531] the more polar, isomer B: compound of Preparation 3.14, to give0.17 g.

[0532] Preparations 3.15 and 3.16

[0533](2S)-1-[5-Chloro-3-(2,5-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0534] (II): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=5-OCH₃; R₅=N(CH₃)₂; n=1; W=O

[0535] [lacuna] Preparation 1.7, 0.5 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 0.3 g of triethylamine in10 ml of DCM [lacuna]. The reaction mixture is washed with 5% NaHCO₃solution and with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with DCM and then with a DCM/MeOH mixture (98/2;v/v). The diasteroisomers are separated:

[0536] the less polar, isomer A: compound of Preparation 3.15, to give0.2 g.

[0537]1the more polar, isomer B: compound of Preparation 3.16, to give0.38 g.

[0538] Preparations 3.17 and 3.18

[0539](2S)-1-[5-Chloro-3-(2,6-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0540] (II): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=6-OCH₃; R₅=N(CH₃)₂; n=1; W=O

[0541] A mixture of 1.9 g of the compound obtained in Preparation 1.8, 1g of (2S)-N,N-dimethyl-pyrrolidine-2-carboxamide and 1 ml oftriethylamine in 20 ml of DCM is left stirring for 3 hours at RT. Thereaction mixture is washed with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/MeOH mixture (98/2;v/v). The diastereoisomers are separated:

[0542] the less polar, isomer A: compound of Preparation 3.17, which iscrystallized from iso ether to give 0.38 g.α_(D)²⁰ = −371^(^(∘))(c = 0.15, chloroform)

[0543] the more polar, isomer B: compound of Preparation 3.18, to give0.4 g.

[0544] Preparations 3.19 and 3.20

[0545](2S)-1-[5-Chloro-3-(3,5-dimethoxyphenyl)-2-oxo-3,4-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0546] (II): R₁=Cl; R₂=H; R₃=3-OCH₃; R₄=5-OCH₃; R₅=N(CH₃)₂; n=1; W=O

[0547] A mixture of 1.4 g of the compound obtained in Preparation 1.9,0.7 g of (2S)-N,N-dimethyl-pyrrolidine-2-carboxamide and 0.8 ml oftriethylamine in 20 ml of DCM is left stirring for 3 hours at RT. Thereaction mixture is washed with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/EtOAc mixture (95/5;v/v). The diastereoisomers are separated:

[0548] the less polar, isomer A: compound of Preparation 3.19, to give0.18 g.

[0549] the more polar, isomer B: compound of Preparation 3.20.

[0550] Preparations 3.21 and 3.22

[0551](2S)-1-[5-Chloro-3-(1,3-benzodioxol-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0552] (II): R₁=Cl; R₂=H; R₃+R₄=2,3-O—CH₂—O—; R₅=N(CH₃)₂; n=1; W=O

[0553] A mixture of 0.61 g of the compound obtained in Preparation 1.10,0.45 g of (2S)-N,N-dimethyl-pyrrolidine-2-carboxamide and 1 ml oftriethylamine in 20 ml of DCM is left stirring for 1 hour at RT. Thereaction mixture is washed with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/MeOH mixture(98.5/1.5; v/v). The diastereoisomers are separated:

[0554] the less polar, isomer A: compound of Preparation 3.21, to give0.19 g; m.p.=241° C.

[0555] the more polar, isomer B: compound of Preparation 3.22.

[0556] Preparations 3.23 and 3.24

[0557](2S)-1-[5-Chloro-3-(2-trifluoromethoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0558] (II): R₁=Cl; R₂=H; R₃=2-OCF₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0559] A mixture of 1.8 g of the compound obtained in Preparation 1.11,1.5 g of (2S)-N,N-dimethyl-pyrrolidine-2-carboxamide and 2 ml of DIPEAin 20 ml of DCM is left stirring for 3 hours at RT. The reaction mixtureis washed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH mixture (99/1; v/v). Thediastereoisomers are separated:

[0560] the less polar, isomer A: compound of Preparation 3.23, to give0.34 g.

[0561] the more polar, isomer B: compound of Preparation 3.24.

[0562] Preparations 3.25 and 3.26

[0563](2S)-1-[5-Chloro-3-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,isomer A and isomer B

[0564] (II): R₁=Cl; R₂=H; R₃=2-F; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0565] A mixture of 1.56 g of the compound obtained in Preparation 1.21,1 g of (2S)-N,N-dimethyl-pyrrolidine-2-carboxamide and 1 ml oftriethylamine in 50 ml of DCM is left stirring for 24 hours at RT. Theprecipitate formed is spin-filtered off and washed with DCM to give 0.62g of the more polar isomer, isomer B: compound of Preparation 3.26;α_(D)²⁰ = +99^(^(∘))(c = 0.15; chloroform).

[0566] The spin-filtration and washing liquors are concentrated undervacuum, the residue is taken up in a minimum amount of DCM, theprecipitate of isomer B formed is spin-filtered off again and thespin-filtration liquor is concentrated under vacuum. The residue ischromatographed on alumina, eluting with a DCM/MeOH mixture (99.5/0.5;v/v). The other isomer is separated out:

[0567] the less polar, isomer A: compound of Preparation 3.25, to give0.42 g. α_(D)²⁰ = −182^(^(∘))(c = 0.14; chloroform).

[0568] Preparation 3.27

[0569](2S)-1-[5-Chloro-3-(2-benzyloxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer

[0570] (II): R₁=Cl; R₂=H; R₃=2-OBzl; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0571] A mixture of 4 g of the compound obtained in Preparation 1.13,1.8 g of (2S)-N,N-dimethyl-pyrrolidine-2-carboxamide and 3 ml oftriethylamine in 20 ml of DCM is left stirring for 12 hours at RT. Thereaction mixture is washed with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue istaken up in a THF/iso ether mixture and left to crystallize. Theprecipitate formed is spin-filtered off to give 2.2 g of the more polarcompound by TLC on alumina, DCM/MeOH (99/1; v/v). The spin-filtrationliquor is chromatographed on alumina, eluting with a DCM/MeOH mixture(99/1; v/v) and a further 0.4 g of the more polar compound is collected.The 2.6 g of the more polar compound thus obtained arere-chromatographed on alumina, eluting with a DCM/MeOH mixture (99/1;v/v). 2.1 g of the expected product are obtained; m.p.=240° C.α_(D)²⁰ = −171^(^(∘))(c = 0.15; chloroform).

[0572] Preparations 3.28 and 3.29

[0573] (2S)1-[5-Chloro-3-(2-methoxy-6-methyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0574] (II): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=6-CH₃; R₅=N(CH₃)₂; n=1; W=O

[0575] A mixture of 1 g of the compound obtained in Preparation 1.14,0.5 g of (2S)-N,N-dimethyl-pyrrolidine-2-carboxamide and 1 ml oftriethylamine in 20 ml of DCM is left stirring for 48 hours. Thereaction mixture is washed with water, with 5% NaHCO₃ solution and withwater, the organic phase is dried over Na₂SO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/MeOH mixture (98/2; v/v). The diastereoisomersare separated:

[0576] the less polar, isomer A: compound of Preparation 3.28, to give0.4 g.

[0577] the more polar, isomer B: compound of Preparation 3.29, to give0.6 g.

[0578] Preparation 3.30

[0579](2S)-1-[5-Trifluoromethoxy-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,the less polar isomer

[0580] (II): R₁=OCF₃; R₂=H; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0581] 0.839 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 0.5 mlof DIPEA are added to the solution of the compound obtained inPreparation 1.15 in DCM and the mixture is then heated at 35° C. for 4hours. The reaction mixture is concentrated under vacuum, the residue istaken up in 5% K₂CO₃ solution and extracted with EtOAc, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed three times successively onalumina, eluting with a DCM/MeOH mixture (98/2; v/v). Thediastereoisomers are separated and the less polar compound is collectedduring the chromatography, but the more polar compound is collected byTLC on alumina, eluting with DCM/MeOH (99.5/0.5; v/v). 0.371 g of theexpected product is obtained.

[0582] Preparation 3.31

[0583](2S)-1-[5,6-Dichloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,mixture of diastereoisomers

[0584] (II): R₁=Cl; R₂=6-Cl; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0585] 0.81 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide is added toa mixture of 1.95 g of the compound obtained in Preparation 1.16 in 25ml of DCM, followed by addition of 2 ml of DIPEA, and the mixture isleft stirring overnight at RT. The reaction mixture is concentratedunder vacuum, the residue is taken up in saturated K₂CO₃ solution andextracted three times with EtOAc, the organic phase is washed threetimes with water and with saturated NaCl solution and dried over Na₂SO₄,and the solvent is evaporated off under vacuum. 1.774 g of the expectedproduct are obtained in the form of a mixture of diasteroisomers aftercrystallization from iso ether.

[0586] Preparation 3.32

[0587](2S)-1-[5,6-Dichloro-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,mixture of diastereoisomers

[0588] (II): R₁=Cl; R₂=6-Cl; R₃=2-Cl; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0589] A mixture of 1 g of the compound obtained in Preparation 1.17 and0.73 g of (2S)-N,N-dimethyl-pyrrolidine-2-carboxamide in 10 ml ofchloroform is left stirring for 48 hours at RT. The reaction mixture isconcentrated under vacuum, the residue is taken up in 5% K₂CO₃ solutionand extracted with EtOAc (presence of a precipitate in the organicphase), the organic phase is washed twice with water, the phases areseparated by settling and THF is added until the precipitate hasdissolved. The solvents are partially concentrated under vacuum to givea precipitate in the EtOAc; iso ether is added until precipitation iscomplete and the precipitate formed is spin-filtered off. 1 g of theexpected product is obtained in the form of the mixture ofdiastereoisomers.

[0590] Preparations 3.33 and 3.34

[0591](2S)-1-[4,5-Dichloro-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0592] (II): R₁=Cl; R₂=4-Cl; R₃=2-Cl; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0593] A solution of 1.5 g of the compound obtained in Preparation 1.18in 15 ml of DCM is cooled on an ice bath, 1.09 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide are added and the mixture isleft stirring for 3 hours at RT. The reaction mixture is concentratedunder vacuum, the residue is taken up in water and extracted with EtOAc,the organic phase is washed with 5% K₂CO₃ solution, with water and withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on alumina,eluting with DCM and then with a DCM/MeOH mixture (98/2; v/v). Thediastereoisomers are separated:

[0594] the less polar, isomer A: compound of Preparation 3.33, which iscrystallized under cold conditions from DCM to give 0.487 g.α_(D)²⁵ = +243.7^(^(∘))(c = 0.2; chloroform)

[0595] the more polar, isomer B: compound of Preparation 3.34, to give0.3 g.

[0596] Preparations 3.35 and 3.36

[0597](2S)-1-[5-Chloro-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0598] (II): R₁=Cl; R₂=6-CH₃; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O.

[0599] 0.95 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and then0.66 g of triethylamine are added at RT to a solution of the compoundobtained in Preparation 1.19 in 20 ml of DCM, and the mixture is leftstirring for 5 minutes at RT. The reaction mixture is poured into 5%K₂CO₃ solution and extracted with EtOAc, and the precipitate formed isspin-filtered off. The precipitate is dissolved in hot THF and thesolution is filtered and combined with the EtOAc organic phase. Thesolvents are partially concentrated under vacuum and the crystallineproduct formed is spin-filtered off [lacuna], the more polar isomer, byTLC on alumina, eluting with DCM/MeOH 98/2; v/v), isomer B: compound ofPreparation 3.36. Isomer B is recrystallized three times from aDCM/EtOAc mixture and is then chromatographed on alumina, eluting with aDCM/MeOH mixture (99.5/0.5; v/v). 0.779 g of isomer B is obtained aftercrystallization from a DCM/iso ether mixture; m.p.=266-269° C.α_(D)²⁵ = −234.5^(^(∘))(c = 0.18; chloroform)

[0600] The spin-filtration liquors from all the above crystallizationsare combined and concentrated under vacuum. The residue ischromatographed on alumina, eluting with a DCM/MeOH mixture (99.5/0.5;v/v) and the other diastereoisomer is separated out:

[0601] the less polar, isomer A: compound of Preparation 3.35, which iscrystallized from a DCM/EtOAc mixture to give 0.47 g; m.p.=257-260° C.α_(D)²⁵ = +122.1^(^(∘))(c = 0.26; chloroform)

[0602] Preparations 3.37 and 3.38

[0603](2S)-1-[5-Chloro-3-(2-chlorophenyl)-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,isomer A and isomer B

[0604] (II): R₁=Cl; R₂=6-OCH₃; R₃=2-Cl; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0605] The solution of the compound obtained in Preparation 1.20 in DCMis cooled on an ice bath, 1.75 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide are added and the mixture isleft stirring for 3 hours while allowing the temperature to return toRT. The reaction mixture is concentrated under vacuum, the residue istaken up in 5% K₂CO₃ solution and extracted with EtOAc containing THFand MeOH, the organic phase is washed with water and with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on alumina, eluting with aDCM/MeOH mixture (99/1; v/v) and then (98/2; v/v). The diastereoisomersare separated:

[0606] the less polar, isomer A: compound of Preparation 3.37, which iscrystallized from a DCM/iso ether mixture to give 0.51 g; m.p.=240-247°C. α_(D)²⁵ = +190.7^(∘)(c = 0.16; chloroform)

[0607] the more polar, isomer B: compound of Preparation 3.38, which iscrystallized from a DCM/MeOH mixture to give 0.664 g; m.p. 239-244° C.α_(D)²⁵ = −289.8^(∘)(c = 0.15; chloroform/MeOH  7/1)

[0608] Preparations 3.39 and 3.40

[0609](2S)-1-[5-Chloro-3-(2-chlorophenyl)-4-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,isomer A and isomer B

[0610] (II): R₁=Cl; R₂=4-OCH₃; R₃=2-Cl; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0611] 1.31 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and then 1.2g of DIPEA are added at RT to the solution of the compound obtained inPreparation 1.21 in DCM. The reaction mixture is concentrated undervacuum, the residue is extracted with EtOAc, the organic phase is washedwith 5% K₂CO₃ solution, with water and with saturated NaCl solution anddried over Na₂SO₄, and the solvent is evaporated off under vacuum. Theresidue is chromatographed on alumina, eluting with a DCM/MeOH mixtureof from (97.5/2.5; v/v) to (97/3; v/v). The diastereoisomers areseparated:

[0612] the less polar, isomer A: compound of Preparation 3.39, which iscrystallized from a DCM/iso ether mixture to give 0.42 g; m.p.=259-260°C. α_(D)²⁵ = +206.9^(∘)(c = 0.13; chloroform)

[0613] the more polar, isomer B: compound of Preparation 3.40, to give0.32 g.

[0614] Preparations 3.41 and 3.42

[0615](2S)-1-[5-Chloro-3-(2-chlorophenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0616] (II): R₁=Cl; R₂=7-F; R₃=2-Cl; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0617] A solution of 1.45 g of(2S)-N,N-dimethyl-pyrrolidine-2-carboxamide in 5 ml of DCM is addeddropwise at RT to a solution of 1.9 g of the compound obtained inPreparation 1.22 in 15 ml of THF, and the mixture is left stirring for12 hours at RT. Water is added to the reaction mixture, the THF and DCMare evaporated off under vacuum, the resulting aqueous phase isextracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, with water and with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on alumina, eluting with DCM and then with a DCM/MeOHmixture (98.5/1.5; v/v). The diastereoisomers are separated:

[0618] the less polar, isomer A: compound of Preparation 3.41, which iscrystallized from a DCM/iso ether/hexane mixture to give 0.612 g;m.p.=246-247° C. α_(D)²⁵ = +194.4^(∘)(c = 0.2; chloroform)

[0619] the more polar, isomer B: compound of Preparation 3.42, to give0.61 g.

[0620] Preparations 3.43 and 3.44

[0621](2S)-1-[6-Chloro-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,isomer A and isomer B

[0622] (II): R₁=CH₃; R₂=6-Cl; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0623] 0.855 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide is added atRT to the solution of the compound obtained in Preparation 1.23 in DCM,and the mixture is left stirring overnight at RT. The reaction mixtureis concentrated under vacuum, the residue is extracted with EtOAc, theorganic phase is washed with 5% K₂CO₃ solution and dried over Na₂SO₄,and the solvent is partially concentrated under vacuum. The crystallineproduct formed is spin-filtered off [lacuna], the more polar isomer, byTLC on alumina, eluting with EtOAc, isomer B: compound of Preparation3.44. 0.32 g of isomer B is obtained after recrystallization from aDCM/EtOAc mixture; m.p.=263° C.α_(D)²⁵ = −256.8^(∘)(c = 0.17; chloroform)

[0624] The above crystallization spin-filtration liquors areconcentrated under vacuum and the residue is chromatographed on alumina,eluting with a DCM/MeOH mixture of from (99.75/0.25; v/v) to (98.5/1.5;v/v). The other diastereoisomer is separated out:

[0625] the less polar, isomer A: compound of Preparation 3.43, which iscrystallized from a DCM/iso ether/hexane mixture; m.p.=257° C.α_(D)²⁵ = +131^(∘)(c = 0.18; chloroform)

[0626] Preparation 3.45

[0627](2S)-1-[4-Chloro-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,diastereoisomer mixture

[0628] (II) R₁=CH₃; R₂=4-Cl; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0629] A mixture of 0.503 g of the compound obtained in Preparation 1.24and 0.476 g of (2S)-N,N-dimethyl-pyrrolidine-2-carboxamide in 5 ml ofDCM is left stirring for 18 hours at RT. The reaction mixture is dilutedby adding 30 ml of DCM, the organic phase is washed with water and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The residueis chromatographed on silica gel, eluting with a DCM/MeOH mixture (96/4;v/v). 0.369 g of the expected product is obtained in the form of amixture of diastereoisomers.

[0630] Preparation 3.46

[0631](2S)-1-[3-(2-Methoxyphenyl)-2-oxo-1,2,3,5,6,7-hexahydrocyclopenta[f]indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,diastereoisomer Mixture

[0632] (II): R₁+R₂=5,6-CH₂CH₂CH₂—; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0633] A mixture of the compound obtained in Preparation 1.25, 1 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml of triethylamine in30 ml of DCM is left stirring for 48 hours at RT. The reaction mixtureis washed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/EtOAc mixture (90/10; v/v). 0.87 g ofthe expected product is obtained after crystallization from a DCM/isoether mixture.

[0634] Preparation 3.47

[0635](2S)-1-[3-(2-Methoxy-6-methylphenyl)-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,the more polar isomer

[0636] (II): R₁=CH₃; R₂=6-CH₃; R₃=2-OCH₃; R₄=6-CH₃; R₅=N(CH₃)₂; n=1; W=O

[0637] 1.43 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and then1.75 ml of DIPEA are added at RT to the suspension of the compoundobtained in Preparation 1.26 in DCM, and the mixture is left stirringovernight. The reaction mixture is concentrated under vacuum, theresidue is taken up in 5% K₂CO₃ solution and extracted with EtOAc, theorganic phase is dried over Na₂SO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica gel, eluting witha DCM/MeOH mixture (96/4; v/v) and the more polar compound is collected.0.127 g of the expected product is obtained after crystallization from aDCM/iso ether mixture; m.p.=194-197° C.

[0638] Preparations 3.48 and 3.49

[0639](2S)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,isomer A and isomer B

[0640] (II): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=1; W=O

[0641] A solution of 2.41 g of the compound obtained in Preparation 2.2and 4 ml of triethylamine in 10 ml of MeOH is added dropwise at RT to asuspension of 1.93 g of the compound obtained in Preparation 1.1 in 19ml of THF, and the mixture is left stirring for 12 hours at RT. Themixture is concentrated under vacuum, the residue is extracted withEtOAc, the organic phase is washed with 5% K₂CO₃ solution, with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM and then with a DCM/MeOH mixture (97/3; v/v). Thediastereoisomers are separated:

[0642] the less polar, isomer A: compound of Preparation 3.48, which isre-chromatographed on alumina, eluting with DCM and then with a DCM/MeOHmixture (97/3; v/v) to give 0.634 g after crystallization from a DCM/isoether mixture; m.p.=229° C. α_(D)²⁵ = +190.9^(∘)(c = 0.188; chloroform)

[0643] the more polar, isomer B: compound of Preparation 3.49, which isre-chromatographed on alumina, eluting with DCM and then with a DCM/MeOHmixture (97/3; v/v) to give 0.987 g after crystallization from a DCM/isoether mixture; m.p.=243° C. α_(D)²⁵ = −182.7^(∘)(c = 0.214; chloroform)

[0644] Preparations 3.50 and 3.51

[0645]1-[5-Chloro-3-(2,5-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,racemic isomer A and racemic isomer B

[0646] (II): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=5-OCH₃; R₅=N(CH₃)₂; n=2; W=O

[0647] A solution of 2.13 g of the compound obtained in Preparation 1.7in 14 ml of DCM is cooled on an ice bath, 2.54 g of the compoundobtained in Preparation 2.3 are added, followed by addition of 1.83 mlof triethylamine, and the mixture is left stirring for 72 hours at RT.Water is added to the reaction mixture, the DCM is evaporated off undervacuum, the aqueous phase is extracted with EtOAc, the organic phase iswashed with 5% K₂CO₃ solution, with water and with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on alumina, eluting with DCM andthen with a DCM/MeOH mixture (99/1; v/v). The two pairs of enantiomersare separated:

[0648] the less polar, racemic isomer A: compound of Preparation 3.50,which is crystallized from a DCM/iso ether/hexane mixture to give 0.606g,; m.p.=217° C.

[0649] the more polar, racemic isomer B: compound of Preparation 3.51.

[0650] Preparation 3.52

[0651](2S)-1-[5,6-Dichloro-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,mixture of diastereoisomers

[0652] (II): R₁=Cl; R₂=6-Cl; R₃=2-Cl; R₄=H; R₅=N(CH₃)₂; n=2; W=O

[0653] 2.66 ml of DIPEA are added to a mixture of 1.5 g of the compoundobtained in Preparation 2.2 in 20 ml of DCM, followed by addition of 3 gof the compound obtained in Preparation 1.17, and the mixture is leftstirring for 10 minutes at RT. The reaction mixture is washed with 5%K₂CO₃ solution and with saturated NaCl solution, the organic phase isdried over Na₂SO₄ and the solvents are concentrated under vacuum. Theresidue is chromatographed on alumina, eluting with a DCM/MeOH mixture(97.5/2.5; v/v). 1.821 g of the expected product are obtained.

[0654] Preparation 3.53

[0655](2S)-1-[5,6-Dichloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,the more polar isomer

[0656] (II): R₁=Cl; R₂=6-Cl; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=2; W=O

[0657] 1.1 g of the compound obtained in Preparation 2.2 are added to amixture of 1.95 g of the compound obtained in Preparation 1.16 in 25 mlof DCM, followed by addition of 2 ml of DIPEA, and the mixture is leftstirring overnight at RT. The mixture is concentrated under vacuum, theresidue is taken up in 5% K₂CO₃ solution and extracted three times withEtOAc, the organic phase is washed with water and with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on alumina, eluting with DCM/MeOH(98/2; v/v). The diastereoisomers are separated and the more polarcompound is collected. 0.821 g of the expected product is obtained.

[0658] Preparations 3.54 and 3.55

[0659](2S)-1-[5-Chloro-3-(2-chlorophenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,isomer A and isomer B

[0660] (II): R₁=Cl; R₂=7-F; R₃=2-Cl; R₄=H; R₅=N(CH₃)₂; n=2; W=O

[0661] 1.6 g of the compound obtained in Preparation 2.2 are added to asolution of 3.4 g of the compound obtained in Preparation 1.22 in 30 mlof DCM, followed by addition of 4 ml of DIPEA, and the mixture is heatedat 40° C. for 4 hours. The mixture is concentrated under vacuum, theresidue is extracted with EtOAc and washed with 5% K₂CO₃ solution, withwater and with saturated NaCl solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with DCM/EtOAc (83/17; v/v) and thenre-chromatographed on alumina, eluting with a gradient of a DCM/MeOHmixture of from (99.25/0.75; v/v) to (96.5/3.5; v/v). Thediasteroisomers are separated:

[0662] the less polar, isomer A: compound of Preparation 3.54, which iscrystallized from ether/hexane to give 0.53 g; m.p.=136° C.α_(D)²⁵ = +200^(∘)(c = 0.1; chloroform)

[0663] the more polar, isomer B: compound of Preparation 3.55, which iscrystallized from iso ether to give 1.51 g; m.p.=233° C.α_(D)²⁵ = −275.8^(∘)(c = 0.12; chloroform)

[0664] Preparations 3.56 and 3.57

[0665](2S)-1-[5-Chloro-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,isomer A and isomer B

[0666] (II): R₁=Cl; R₂=6-CH₃; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=2; W=O

[0667] A mixture of 1.97 g of the compound obtained in Preparation 1.19,1.25 g of the compound obtained in Preparation 2.2 and 2.2 ml of DIPEAin 25 ml of DCM is left stirring overnight at RT. The mixture isconcentrated under vacuum, extracted with EtOAc, washed with 5% K₂CO₃solution and with water and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on alumina,eluting with DCM/MeOH (99/1; v/v). The diastereoisomers are separated:

[0668] the less polar, isomer A: compound of Preparation 3.56, to give0.92 g; m.p.=228-229° C.α_(D)²⁵ = +197.5^(∘)  (c = 0.125; chloroform)

[0669] the more polar, isomer B: compound of Preparation 3.57, to give1.527 g.

[0670] Preparations 3.58 and 3.59

[0671](2S)-1-[5-Chloro-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,isomer A and isomer B

[0672] (II): R₁=Cl; R₂=6-CF₃; R₃=2-OCH₃; R₄=H; R₅=N(CH₃)₂; n=2; W=O

[0673] 0.5 g of the compound obtained in Preparation 2.2 and 0.9 ml oftriethylamine are added at RT to a solution of 1.2 g of the compoundobtained in Preparation 1.27 in 7 ml of DCM, and the mixture is leftstirring for 18 hours. Water is added to the reaction mixture, the DCMis evaporated off under vacuum, the aqueous phase is extracted withEtOAc, the organic phase is washed with 5% K₂CO₃ solution, with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed onalumina, eluting with a DCM/MeOH mixture (99/1; v/v). Thediastereoisomers are separated:

[0674] the less polar, isomer A: compound of Preparation 3.58, which iscrystallized from DCM/iso ether to give 0.611 g; m.p.=241-242° C.α_(D)²⁵ = +204.63^(∘)  (c = 0.216; chloroform)

[0675] the more polar, isomer B: compound of Preparation 3.59, to give0.77 g.

[0676] Preparations 3.60 and 3.61

[0677]1-[3-(2-Chlorophenyl)-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,racemic isomer A and racemic isomer B

[0678] (II): R₁=CH₃; R₂=6-CH₃; R₃=2-Cl; R₄=H; R₅=N(CH₃)₂; n=2; W=O

[0679] 20 ml of DCM, 1.6 g of the compound obtained in Preparation 2.3and 2.7 g of DIPEA are added to the solution of the compound obtained inPreparation 1.28 and the mixture is then heated at 45° C. for 3 hours.The mixture is concentrated under vacuum, the residue is taken up in 5%K₂CO₃ solution and extracted with EtOAc, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on alumina, eluting with a DCM/MeOH mixture of from(99.5/0.5; v/v) to (98/2; v/v). The two pairs of enantiomers areseparated:

[0680] the less polar, racemic isomer A: compound of Preparation 3.60,which is crystallized from DCM/iso ether to give 0.31 g; m.p.=168-170°C.

[0681] the more polar, racemic isomer B: compound of Preparation 3.61,which is crystallized from DCM/iso ether to give 1.03 g.

EXAMPLE 1

[0682](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer

[0683] (I): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=H; R₅=—N(CH₃)₂; R₆=2-OCH₃;R₇=OCH₃; n=1; W=O

[0684] A suspension of 3.76 g of the compound obtained in Preparation3.1 in 35 ml of DMF is cooled on an ice bath, 0.407 g of 60% sodiumhydride in oil is added, under an argon atmosphere, and the mixture iswarmed to RT and left stirring until dissolved. The reaction mixture iscooled on an ice bath, 2.35 g of 2,4-dimethoxybenzenesulphonyl chlorideare added and the mixture is left stirring for 3 hours 30 minutes at RT.5% K₂CO₃ solution is added, the mixture is extracted with EtOAc, theorganic phase is washed with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue isdissolved in DCM, iso ether and hexane are added, the solvents arepartially concentrated under vacuum at RT and the precipitate formed isspin-filtered off. 3.8 g of the expected product are obtained.α_(D)²⁰ = −226.9^(∘)  (c = 0.2; chloroform)

[0685]¹H NMR: d₆-DMSO: δ (ppm): 1.0 to 1.7: 2mt: 4H; 1.9 to 3.7: mt+2bs:8H; 3.2: s: 3H; 3.7: s: 3H; 4.3: d: 1H; 6.6: mt: 2H; 6.8: mt: 3H; 7.1:t: 1H; 7.3: dd: 1H; 7.5: d: 1H; 7.6: d: 1H; 7.8: d: 1H.

EXAMPLE 2

[0686](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethylpyrrolidine-2-carboxamide,laevorotatory isomer

[0687] (I): R₁ Cl; R₂=H; R₃₂—OCH₃; R₄=H; R₅=—NHCH₂CH₃; R₆=2-OCH₃;R₇=OCH₃; n=1; W=O

[0688] A) tert-Butyl(2S)-1-[5-chloro-1-[(2,4-dimethoxy-phenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylate,laevorotatory Isomer

[0689] A solution of 3.25 g of the compound obtained in Preparation 3.2in 30 ml of DMF is cooled on an ice bath, 0.323 g of 60% sodium hydridein oil is added, under an argon atmosphere, and the mixture is leftstirring for 20 minutes. 1.9 g of 2,4-dimethoxybenzene-sulphonylchloride are then added and the mixture is left stirring for 4 hours atRT. Water is added to the reaction mixture, the resulting mixture isextracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, with water and with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with DCM and then with a DCM/MeOHmixture (99/1; v/v). 3.37 g of the expected product are obtained aftercrystallization from a DCM/iso ether mixture; m.p.=136° C.α_(D)²⁵ = −190.25^(∘)  (c = 0.195; chloroform)

[0690] B)(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylicacid

[0691] A mixture of 1.8 g of the compound obtained in the preceding stepin 20 ml of a 4N solution of HCl in dioxane is left stirring overnightat RT. The mixture is concentrated under vacuum, the residue is taken upin DCM and the solvent is evaporated off under vacuum. 1.64 g of theexpected product are obtained and are used without further purification.

[0692] C)(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

[0693] A mixture of 0.5 g of the compound obtained in the precedingstep, 0.44 g of PyBOP and 0.108 g of DIPEA in 5 ml of DCM and 1 ml ofTHF is left stirring for 5 minutes at RT, followed by addition of 0.11 gof a 70% solution of ethylamine in water, and the mixture is leftstirring for 2 hours at RT. The mixture is concentrated under vacuum,the residue is extracted with EtOAc, the organic phase is washed with 5%K₂CO₃ solution, with water and with saturated NaCl solution and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The residueis chromatographed on alumina, eluting with a DCM/MeOH mixture (99/1;v/v). 0.315 g of the expected product is obtained after crystallizationfrom a DCM/iso ether mixture.α_(D)²⁵ = −151.8^(∘)  (c = 0.22; chloroform)

[0694]¹H NMR: d₆-DMSO: δ (ppm): 1.0: t: 3H; 1.2 to 1.5: mt: 4H; 2.0 and2.6: q+t: 2H; 3.0: mt: 2H; 3.4: s: 3H; 3.6: s: 3H; 3.8: bs: 4H; 6.6:s+dd: 2H; 6.8: 2d: 2H; 7.2: mt: 2H; 7.4: dd: 1H; 7.6: 3d+s: 4H.

EXAMPLE 3

[0695](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(azetidin-1-ylcarbonyl)pyrrolidine,Laevorotatory Isomer

[0696] (I): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=H;

[0697] R₆=2-OCH₃; R₇=OCH₃; n=1; W=O.

[0698] A mixture of 0.56 g of the compound obtained in step B of Example2, 0.496 g of PyBOP and 0.114 g of DIPEA in 5 ml of DCM and 1 ml of THFis left stirring for 5 minutes at RT, followed by addition of 0.18 g ofazetidine hydrochloride and 0.22 g of DIPEA, and the mixture is leftstirring for 3 hours at RT. The mixture is concentrated under vacuum,the residue is taken up in 5% K₂CO₃ solution and extracted with EtOAc,the organic phase is washed three times with 0.5 N HCl solution and withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/MeOH mixture (98/2; v/v). 0.32 g of the expectedproduct is obtained after crystallization from an ether/iso ether/hexanemixture;

[0699] m.p.=161-166° C. α_(D)²⁵ = −169.8^(∘)  (c = 0.19; chloroform)

EXAMPLE 4

[0700](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carbothioamide,Laevorotatory Isomer

[0701] (I): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=H; R₅=-N(CH₃)₂; R₆=2-OCH₃;R₇=OCH₃; n=1; W=S

[0702] A mixture of 0.27 g of the compound obtained in Preparation 3.3in 5 ml of DMF is cooled to 4° C., 0.026 g of 60% sodium hydride in oilis added, under a nitrogen atmosphere, and the mixture is left stirringfor 15 minutes at 4° C. 0.139 g of 2,4-dimethoxybenzene-sulphonylchloride is then added and the mixture is left stirring for 3 hours atRT. 50 ml of water are added to the reaction mixture, the resultingmixture is extracted with EtOAc, the organic phase is washed with 5%Na₂CO₃ solution, with saturated NaCl solution and with water and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The residueis chromatographed on silica gel, eluting with a DCM/EtOAc mixture(97/3; v/v). 0.18 g of the expected product is obtained aftercrystallization from a DCM/iso ether mixture; m.p.=164° C.α_(D)²⁵ = −25^(∘)  (c = 0.2; chloroform)

[0703]¹H NMR: d₆-DMSO: δ (ppm): 1.3 to 2.2: 4mt: 4H; 2.4 and 3.0: 2mt:2H; 2.7: s: 3H; 3.2: s: 3H; 3.4: s: 3H; 3.7: s: 3H; 3.9: s: 3H; 4.9: dd:1H; 6.7: mt: 2H; 6.9: mt: 3H; 7.3: dt: 1H; 7.4: dd: 1H; 7.8; d: 1H; 7.9:d: 1H; 8.0: d: 1H

EXAMPLE 5

[0704] Methyl(2S)-1-[5-chloro-1-[(2,4-dimethoxy-phenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylate,Laevorotatory Isomer

[0705] (I): R₁=Cl; R₂H; R₃₂—OCH₃; R₄=H; R₅=—OCH₃; R₆=2-OCH₃; R₇=OCH₃;n=1; W=O

[0706] A solution of 0.793 g of the compound obtained in Preparation 3.4in 8 ml of DMF is cooled to 0° C., 0.096 g of 60% sodium hydride in oilis added, under an argon atmosphere, and the mixture is left stirringuntil the evolution of gas has ceased. 0.564 g of2,4-dimethoxybenzenesulphonyl chloride is then added and the mixture isleft stirring for 3 hours at RT. The reaction mixture is poured intowater and extracted with EtOAc, the organic phase is washed with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/EtOAc mixture (97/3; v/v). The fractionscontaining only the more polar compound are collected. 0.495 g of theexpected product is obtained after crystallization from a DCM/isoether/ether mixture; m.p.=178=180° C.

[0707] α_(D) ²⁵=−197.3° (c=0.19; chloroform)

EXAMPLE 6

[0708](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

[0709] (I): R₁=Cl; R₂=H; R₃=2-OCH₂CH₃; R₄=H; R₅=—N(CH₃)₂; R₆=2-OCH₃;R₇=OCH₃; n=1; W=O

[0710] 0.11 g of 60% sodium hydride in oil is added portionwise at RT toa mixture of 0.52 g of the compound obtained in Preparation 3.6 (isomerB) in 20 ml of THF, and the mixture is left stirring for 15 minutes atRT. 0.29 g of 2,4-dimethoxybenzene-sulphonyl chloride is then added andthe mixture is left stirring for 1 hour at RT. The reaction mixture ispoured into 100 ml of water and extracted with EtOAc, the organic phaseis washed with water and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/MeOH mixture (99/1; v/v). 0.54 g of the expectedproduct is obtained after crystallization from iso ether; m.p.=145° C.α_(D)²⁰ = −205^(∘)  (c = 0.15; chloroform)

EXAMPLE 7

[0711](2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

[0712] (I): R₁=Cl; R₂=H; R₃=2-OH; R₄=H; R₅=—N(CH₃)₂; R₆=2-OCH₃; R₇=OCH₃;n=1; W=O

[0713] A)(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-benzyloxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

[0714] 0.2 g of 60% sodium hydride in oil is added portionwise at RT toa mixture of 2 g of the compound obtained in Preparation 3.27 in 50 mlof THF, and the mixture is left stirring for 15 minutes. 1.2 g of2,4-dimethoxybenzenesulphonyl chloride are then added and the mixture isleft stirring for 30 minutes at RT. The reaction mixture is poured intowater and extracted with EtOAc, the organic phase is dried over Na₂SO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/EtOAc mixture (95/5;v/v). 2.25 g of the expected product are obtained after crystallizationfrom iso ether. α_(D)²⁰ = −245^(∘)  (c = 0.14; chloroform)

[0715] B)(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

[0716] 1.2 g of the compound obtained in the preceding step, 1 ml oftrifluoroacetic acid, 0.5 ml of thioanisole and 10 ml oftrifluoromethanesulphonic acid are mixed together at a temperature below5° C. and the mixture is left stirring while allowing the temperature toreturn to RT and is then stirred for 15 minutes at RT. The reactionmixture is poured into an ice/water mixture and extracted with EtOAc,the organic phase is washed with water, with 5% NaHCO₃ solution and withwater and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with aDCM/MeOH mixture (99/1; v/v). 0.6 g of the expected product is obtained;m.p.=143° C. α_(D)²⁰ = −94^(∘)  (c = 0.12; chloroform)

[0717]¹H NMR: d₆-DMSO: δ (ppm): 1.4 to 2.0: 2up: 4H; 2.4 and 3.0: up+2s:7H; 3.4 to 4.0: 2s: 7H; 4.5: mt: 1H; 6.8 to 7.4: up: 7H; 7.6: dd: 1H;7.9 to 8.1: 2d: 2H; 10.0: bs: 1H

EXAMPLE 8

[0718](2S)-1-[5-Trifluoromethoxy-1-[(2,4-dimethoxy-phenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

[0719] (I): R₁=OCF₃; R₂=H; R₃=2-OCH₃; R₄=H; R₅=-N(CH₃)₂; R₆=2-OCH₃;R₇=OCH₃; n=1; W=O

[0720] 0.035 g of 60% sodium hydride in oil is added at RT, under anargon atmosphere, to a solution of 0.371 g of the compound obtained inPreparation 3.30 in 5 ml of DMF, and the mixture is left stirring for 15minutes. 0.208 g of 2,4-dimethoxybenzenesulphonyl chloride is then addedand the mixture is left stirring for 3 hours at RT. The reaction mixtureis poured into 5% K₂CO₃ solution and extracted with EtOAc, the organicphase is washed with saturated NaCl solution and dried over Na₂SO₄ andthe solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/EtOAc mixture (80/20;v/v). The residue is dissolved in a minimum amount of MeOH, thissolution is poured into water and the precipitate formed isspin-filtered off. 0.335 g of the expected product is obtained afterdrying. α_(D)²⁵ = −239^(∘)  (c = 0.17; chloroform/MeOH, 8/2; v/v)

[0721] chloroform/MeOH, 8/2; v/v)

[0722]¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 2.0: 2up: 2H; 2.1 to 2.8: 2s+up:8H; 3.4: s: 3H; 3.6: s: 3H; 3.9: s: 3H; 4.5: d: 1H; 6.7 to 7.0: 2up: 5H;7.2: dt: 1H; 7.4: dd: 1H; 7.7: dd: 1H; 7.9: d: 1H; 8.0: d: 1H

EXAMPLES 9 and 10

[0723](2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxy-phenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,isomer A and isomer B

[0724] (I): R₁=Cl; R₂=6-Cl; R₃=2-OCH₃; R₄=H; R₅=-N(CH₃)₂; R₆=2-OCH₃;R₇=OCH₃; n=1; W=O

[0725] A mixture of 1.769 g of the compound obtained in Preparation 3.31in 17 ml of DMF is cooled on an ice bath, 0.187 g of 60% sodium hydridein oil is added, under an argon atmosphere, and the mixture is leftstirring for 10 minutes. 1.058 g of 2,4-dimethoxy-benzenesulphonylchloride are then added and the mixture is left stirring for 3 hours atRT. Water is added and the reaction mixture is extracted with EtOAc, theorganic phase is washed with water and with saturated NaCl solution anddried over Na₂SO₄, and the solvent is evaporated off under vacuum. Theresidue is chromatographed on alumina, eluting with a DCM/hexane mixture(90/10; v/v). The diastereoisomers are separated:

[0726] the less polar, isomer A: compound of Example 9, which iscrystallized from iso ether to give 0.308 g; m.p.=193-194° C.α_(D)²⁰ = +128.1^(∘)  (c = 0.149  chloroform)

[0727] the more polar, isomer B: compound of Example 10, which iscrystallized from iso ether and DCM to give 0.821 g; m.p. 231-232° C.α_(D) ²⁰=−95.7° (c=0.116; chloroform)

EXAMPLE 11

[0728](2S)-1-[6-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

[0729] (I): R₁=CH₃; R₂=6-Cl; R₃=2-OCH₃; R₄=H; R₅=—N(CH₃)₂; R₆=2-OCH₃;R₇=OCH₃; n=1; W=O

[0730] A suspension of 0.295 g of the compound obtained in Preparation3.44 (isomer B) in 3 ml of DMF is cooled to 0° C., 0.03 g of 60% sodiumhydride in oil is added, under an argon atmosphere, and the mixture isleft stirring for 10 minutes. 0.18 g of 2,4-dimethoxy-benzenesulphonylchloride is then added and the mixture is left stirring for 3 hours atRT. Water is added and the reaction mixture is extracted with EtOAc, theorganic phase is washed with 5% K₂CO₃ solution, with water and withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM and then with a DCM/EtOAc mixture (98/2; v/v). Theproduct obtained is taken up in an iso ether/hexane mixture and theprecipitate formed is spin-filtered off. 0.193 g of the expected productis obtained; m.p.=204-206° C.

[0731] α_(D) ²⁵=−211.2° (c=0.11; chloroform)

[0732]¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 2.2: up: 6H; 2.3: s: 3H; 2.4 and2.8: 2s: 6H; 3.5: s: 3H; 3.8: s: 3H; 4.0: s: 3H; 4.5: d: 1H; 6.8 to 7.2:up: 5H; 7.3: dt: 1H; 7.7: dd: 1H; 7.8: s: 1H; 8.1: d: 1H

EXAMPLE 12

[0733]1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide

[0734] (I): R₁=Cl; R₂=H; R₃=2-OCH₃; R₄=5-OCH₃; R₅=—N(CH₃)₂; R₆=2-OCH₃;R₇=OCH₃; n=2; W=O

[0735] This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.51(racemic isomer B). The product is chromatographed on silica gel,eluting with a DCM/MeOH mixture (98/2; v/v). The expected product isobtained after crystallization from a DCM/iso ether mixture;m.p.=212-214° C.

EXAMPLES 13 and 14

[0736](2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,isomer A and isomer B

[0737] (I): R₁=Cl; R₂=6-Cl; R₃=2-Cl; R₄=H; R₅=N(CH₃)₂; R₆=2-OCH₃;R₇=OCH₃; n=2; W=O

[0738] These compounds are prepared according to the procedure describedin Examples 9 and 10, starting with 1.821 g of the compound obtained inPreparation 3.52. The product is chromatographed on alumina, elutingwith DCM and then with a DCM/MeOH mixture (95/5; v/v). Thediastereoisomers are separated:

[0739] the less polar, isomer A: compound of Example 13, which iscrystallized from DCM/heptane to give 0.824 g.α_(D)²⁵ = +257.1^(∘)  (c = 0.105; chloroform)

[0740] the more polar, isomer B: compound of Example 14, which iscrystallized from iso ether to give 2.032 g; m.p.=257-258° C.α_(D)²⁵ = −353.7^(∘)  (c = 0.108; chloroform)

EXAMPLE 15

[0741]1-[3-(2-Chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide

[0742] (I): R₁=CH₃; R₂=6-CH₃; R₃=2-Cl; R₄=H; R₅=-N(CH₃)₂; R₆=2-OCH₃;R₇=OCH₃; n=2; W=O

[0743] This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.61(racemic isomer B). The product is chromatographed on silica gel,eluting with a DCM/MeOH mixture (98/2; v/v). The expected product isobtained after crystallization from a DCM/iso ether mixture;m.p.=268-270° C.

[0744] Working according to the procedures described in the aboveexamples, starting with the compounds of formula (II) described inPreparations 3 and 2,4-dimethoxybenzenesulphonyl chloride, the compoundsaccording to the invention collated in Table I below are prepared. TABLEI (I)

m.p. ° C.; NMR crystallization Exam- solvent; ples n R₁ R₂ R₃ R₄ α_(D)²⁰ (chloroform) 16 1 Cl H 3-OCH₃ H — (a) — −87° (c = 0.15) 17 1 Cl H4-OCH₃ H — (b) — −238° (c = 0.14) 18 1 Cl H 2-OCH₃ 3-OCH₃ 178.5; NMR (c)iso ether −68° (c = 0.15) 19 1 Cl H 2-OCH₃ 4-OCH₃ 146; NMR (d) — −216°(c = 0.15) 20 1 Cl H 2-OCH₃ 5-OCH₃ — (e) — −266.7° (c = 0.15) 21 1 Cl H2-OCH₃ 6-OCH₃ 213 (f) — −303° (c = 0.13) 22 1 Cl H 3-OCH₃ 5-OCH₃ — (g) —−226° (c = 0.15) 23 1 Cl H 2,3- NMR (h) O—CH₂—O— — −81° (c = 0.14) 24 1Cl H 2-OCF₃ H — (i) — −218° (c = 0.14) 25 1 Cl H 2-F H 196 (j) iso ether−272° (c = 0.14) 26 1 Cl H 2-OCH₃ 6-CH₃ 193; NMR (k) iso ether −250° (c= 0.15) 27 1 Cl 6-Cl 2-Cl H 288 (l) DCM/iso ether −328° (c = 0.23) 28 1Cl 4-Cl 2-Cl H 275-278 (m) DCM/iso ether −321° (c = 0.13) 29 1 Cl 6-CH₃2-OCH₃ H 207-210 (n) iso ether/hexane −191° (c = 0.16) 30 1 Cl 6-OCH₃2-Cl H 278 (dec.); NMR (o) DCM/iso ether −318° (c = 0.16) 31 1 Cl 4-OCH₃2-Cl H 212 (p) DCM/iso ether −269° (c = 0.117) 32 1 Cl 7-F 2-Cl H — (q)DCM/iso ether/hexane −206.8° (c = 0.1) 33 1 CH₃ 4-Cl 2-OCH₃ H NMR (r)DCM/iso ether/hexane −266° (c = 0.11) 34 1 5,6- 2-OCH₃ H 160 (s)CH₂CH₂CH₂— iso ether −174° (c = 0.15) 35 1 CH₃ 6-CH₃ 2-OCH₃ 6-CH₃ 235;NMR (t) DCM/iso ether — 36 2 Cl H 2-OCH₃ H 148-149; NMR (u) DCM/isoether −211° (c = 0.209) 37 2 Cl 6-Cl 2-OCH₃ H 239-240; NMR (v) DCM/isoether −289.3° (c = 0.102) 38 2 Cl 7-F 2-Cl H 149-152 (w) DCM/iso ether−196.2° (c = 0.1) 39 2 Cl 6-CH₃ 2-OCH₃ H 236-237; NMR (x) DCM/iso ether−219.2° (c = 0.105) 40 2 Cl 6-CF₃ 2-OCH₃ H 229 (y) DCM/iso ether/hexane−209.47° (c = 0.243)

[0745] (a) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.7 (isomer A). The product is chromatographed on silicagel, eluting with a DCM/MeOH mixture (99.5/0.5; v/v).

[0746] (b) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.9 (isomer A). The product is chromatographed on silicagel, eluting with DCM.

[0747] (c) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.12 (isomer B). The product is chromatographed on silicagel, eluting with a DCM/EtOAc mixture (95/5; v/v).

[0748] (d) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.13 (isomer A). The product is chromatographed on silicagel, eluting with a DCM/MeOH mixture (99/1; v/v).

[0749] (e) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.15 (isomer A). The product is chromatographed on silicagel, eluting with a DCM/EtOAc mixture (95/5; v/v).

[0750] (f) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.17 (isomer A). The product is chromatographed on silicagel, eluting with a DCM/EtOAc mixture (95/5; v/v).

[0751] (g) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.19 (isomer A). The product is chromatographed on silicagel, eluting with a DCM/MeOH mixture (99.5/0.5; v/v).

[0752] (h) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.21 (isomer A). The product is chromatographed on alumina,eluting with DCM.

[0753] (i) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.23 (isomer A). The product is chromatographed on silicagel, eluting with a DCM/MeOH mixture (99.5/0.5; v/v).

[0754] (j) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.25 (isomer A). The product is chromatographed on silicagel, eluting with a DCM/MeOH mixture (99/1; v/v).

[0755] (k) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.29 (isomer B). The product is chromatographed on silicagel, eluting with a DCM/EtOAc mixture (95/5; v/v).

[0756] (l) This compound is prepared according to the proceduredescribed in Examples 9 and 10, starting with the compound obtained inPreparation 3.32. The product is chromatographed on alumina, elutingwith a DCM/hexane mixture (90/10; v/v), the fractions enriched in thepolar isomer are collected and this product is crystallized from aDCM/iso ether mixture.

[0757] (m) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.34 (isomer B). The product is chromatographed on silicagel, eluting with a DCM/MeOH mixture (99/1; v/v).

[0758] (n) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.36 (isomer B). The product is chromatographed on silicagel, eluting with a DCM/EtOAc mixture (80/20; v/v).

[0759] (o) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.38 (isomer B). The product is chromatographed on silicagel, eluting with a DCM/MeOH mixture (98/2; v/v).

[0760] (p) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.40 (isomer B). The product is chromatographed on alumina,eluting with a DCM/MeOH mixture (99.5/0.5; v/v) and then on silica,eluting with a DCM/MeOH mixture (98/2; v.v).

[0761] (q) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.42 (isomer B). The product is chromatographed on silicagel, eluting with DCM and then with a DCM/MeOH mixture (98.5/1.5; v/v).

[0762] (r) This compound is prepared according to the proceduredescribed in Examples 9 and 10, starting with the compound obtained inPreparation 3.45. The product is chromatographed on silica gel, elutingwith a DCM/MeOH mixture of from (99/1; v/v) to (98/2; v/v) and is thenre-chromatographed on silica gel, eluting with a DCM/MeOH mixture (99/1;v/v) and the less polar compound is collected each time.

[0763] (s) This compound is prepared according to the proceduredescribed in Example 6, starting with the compound obtained inPreparation 3.46. The product is chromatographed on silica gel, elutingwith a DCM/EtOAc mixture (95/5; v/v) and the less polar compound iscollected.

[0764] (t) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.47. The product is chromatographed on silica gel, elutingwith a DCM/MeOH mixture (98/2; v/v).

[0765] (u) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.49 (isomer B). The product is chromatographed on silicagel, eluting with DCM and then with a DCM/EtOAc mixture (85/15; v/v).

[0766] (v) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.53. The product is chromatographed on silica gel, elutingwith a DCM/EtOAc mixture (70/30; v/v).

[0767] (w) This compound is prepared according to the proceduredescribed in Example 8, starting with the compound obtained inPreparation 3.55 (isomer B). The product is chromatographed on silicagel, eluting with a DCM/MeOH mixture (98/2; v/v).

[0768] (x) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.57 (isomer B). The product is chromatographed on silicagel, eluting with a DCM/EtOAc mixture (70/30; v/v).

[0769] (y) This compound is prepared according to the proceduredescribed in Example 11, starting with the compound obtained inPreparation 3.59 (isomer B). The product is chromatographed on silicagel, eluting with DCM and then with a DCM/EtOAc mixture (90/10; v/v).

EXAMPLE 18

[0770]¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 1.8: 2mt 4H; 2.1 to 2.8: mt+3s:11H; 3.6 to 4.0: 3s: 9H; 4.5: mt: 1H; 6.6 to 7.2: mt: 5H; 7.3: t+dd: 1H;7.4: mt: 1H; 7.9: dd+t: 1H; 8.1: d: 1H.

EXAMPLE 19

[0771]¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 2.0: 2mt 4H; 2.2 to 2.8: mt+2s:8H; 3.5: s: 3H; 3.7: s: 3H; 3.8: s: 3H; 4.0: s: 3H; 4.6: d: 1H; 6.5: mt:2H; 6.8: mt: 2H; 7.0: d: 1H; 7.5: dd: 1H; 7.6: d: 1H; 7.9: d: 1H; 8.1:d: 1H.

EXAMPLE 23

[0772]¹H NMR: d₆-DMSO: δ (ppm): 1.4 to 1.9: 2mt 4H; 2.2 to 3.0: 2s+mt:8H; 3.4: s: 3H; 3.8: s: 3H; 4.4: dd: 1H; 5.3 and 5.6: 2s: 2H; 6.6 to7.0: mt: 5H; 7.2: d: 1H; 7.4: dd: 1H; 7.9 to 8.0: 2d: 2H.

EXAMPLE 26

[0773]¹H NMR: d₆-DMSO: δ (ppm): 1.1 to 1.8: m: 4H 2.0: bs: 3H; 2.4: s:3H; 2.5 to 2.7: mt+3s: 5H; 3.3 to 3.9: 4s: 12H; 4.2 and 4.5: 2d: 1H;6.6: mt: 4H; 7.0 to 7.2: mt: 2H; 7.3: 2dd: 1H; 7.6: 2d: 1H; 8.0: mt: 1H.

EXAMPLE 30

[0774]¹H NMR: d₆-DMSO: δ (ppm): 1.3 to 1.9: 2mt 4H; 2.2 to 3.0: up: 8H;3.6: s: 3H; 3.9: s: 3H; 4.1: s: 3H; 4.5: t: 1H; 6.7: mt: 2H; 6.9: s: 1H;7.3: up: 3H; 7.6: bs: 1H; 8.0: d: 2H.

EXAMPLE 33

[0775]¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 1.9: 2mt 4H; 2.2: s: 3H; 2.5: s:3H; 2.5 to 3.6: 2bs: 8H; 3.7: s: 3H; 3.9: s: 3H; 4.5: d: 1H; 6.7: mt:1H; 6.8: mt: 1H; 7.2: dt: 1H; 7.4: d: 1H; 7.7: d: 1H; 7.8: d: 1H; 8.0:d: 1H.

EXAMPLE 35

[0776]¹H NMR: d₆-DMSO: δ (ppm): 1.0 to 2.0: 2up 4H; 2.0 to 3.0: mt: 17H;3.3 to 3.9: 4s: 9H; 4.2 and 4.6: 2d: 1H; 6.6: up: 4H; 7.0: up: 2H; 7.6:S: 1H; 8.0: mt: 1H.

EXAMPLE 36

[0777]¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 1.8: up 6H; 2.2: bs: 2H; 2.5 to2.8: 2bs: 6H; 3.8: s: 3H; 3.9: bs: 4H; 6.7: mt: 4H; 7.0: t: 1H; 7.2: t:1H; 7.4: dd: 1H; 7.9: d: 1H; 8.0: d: 1H.

EXAMPLE 37

[0778]¹H NMR: d₆-DMSO: δ (ppm): 1.1 to 2.0: up 8H; 2.1 to 2.7: 2bs: 7H;2.8: s: 3H; 3.8: s: 3H; 4.0: s: 3H; 6.8: mt: 3H; 6.9: s: 1H; 7.0: t: 1H;7.2: t: 1H;, 7.8: d: 1H; 7.9 to 8.0: d+s: 2H.

EXAMPLE 39

[0779]¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 1.8: 2mt 6H; 2.2: bs: 6H; 2.3: s:3H; 2.6: bs: 2H; 2.7: s: 3H; 3.8: s: 3H; 3.9: bs: 4H; 6.6: mt: 4H; 7.0:t: 1H; 7.2: t: 1H; 7.7: S: 1H; 7.8: d: 1H; 8.0: d: 1H.

1. Compound of formula:

in which: n is 1 or 2; W represents an oxygen atom or a sulphur atom; R₁represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; atrifluoromethyl radical; a trifluoromethoxy radical; R₂ represents ahydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; atrifluoromethyl radical; or R₂ is in position -6- of the indol-2-onering and R₁ and R₂ together represent a trimethylene radical; R₃represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a (C₁-C₂)alkoxy;a trifluoromethoxy radical; R₄ represents a hydrogen atom; a halogenatom; a (C₁-C₂)alkyl; a (C₁-C₂)alkoxy; or R₃ is in position -2- of thephenyl, R₄ is in position -3- of the phenyl and R₃ and R₄ togetherrepresent a methylenedioxy radical; R₅ represents an ethylamino group; adimethylamino group; a 1-azetidinyl radical; a (C₁-C₂)alkoxy; R₆represents a (C₁-C₄)alkoxy; R₇ represents a (C₁-C₄)alkoxy; as well asthe solvates and/or hydrates thereof.
 2. Compound according to claim 1,in the form of optically pure isomers.
 3. Compound according to claim 2,of formula:

in which: the carbon atom bearing the substituent —C(W)R₅ has the (S)configuration and the carbon atom in position -3-of the indol-2-one haseither the (R) configuration or the (S) configuration.
 4. Compoundaccording to claim 3, in the form of the laevorotatory isomer. 5.Compound according to any one of claims 1 to 4, in which: n is 1 or 2; Wrepresents an oxygen atom; R₁ represents a chlorine atom or a methylradical; R₂ represents a hydrogen atom or is in position -6-of theindol-2-one and represents a chlorine atom, a methyl radical, a methoxyradical or a trifluoromethyl radical; R₃ is in position -2- of thephenyl and represents a methoxy radical, a chlorine atom or a fluorineatom; R₄ represents a hydrogen atom, a methyl radical or a methoxyradical; or R₃ is in position -2- of the phenyl, R₄ is in position -3-of the phenyl and R₃ and R₄ together represent a methylenedioxy radical;R₅ represents a dimethylamino group or a methoxy radical; R₆ is inposition -2- of the phenyl and represents a methoxy radical; R₇represents a methoxy radical; as well as the solvates and/or hydratesthereof.
 6. Compound chosen from:(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[6-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,6-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[3-(1,3-Benzodioxol-4-yl)-5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-3-(2-fluorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxy-6-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5,6-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[4,5-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide, laevorotatory isomer;(2S)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5,6-Dimethyl-3-(2-methoxy-6-methyl-phenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer; as well as the solvates and/or hydrates thereof.7. Process for preparing the compounds of formula (I) according to claim1, solvates thereof and/or hydrates thereof, characterized in that: acompound of formula:

in which n, W, R₁, R₂, R₃, R₄ and R₅ are as defined for a compound offormula (I) in claim 1, is reacted, in the presence of a base, with ahalide of formula:

in which R₆ and R₇ are as defined for a compound of formula (I) in claim1 and Hal represents a halogen atom.
 8. Process for preparing thecompounds of formula (I) according to claim 1, in which R₅ represents anethylamino group, a dimethylamino group or a 1-azetidinyl radical and Wrepresents an oxygen atom, solvates thereof and/or hydrates thereof,characterized in that: a) a compound of formula:

in which n, R₁, R₂, R₃ and R₄ are as defined for a compound of formula(I) in claim 1, is reacted, in the presence of a base, with a halide offormula:

in which R₆ and R₇ are as defined for a compound of formula (I) in claim1, to give a compound of formula:

b) the compound of formula (I′) is hydrolysed by the action of an acidto give a compound of formula:

c) the compound of formula (I″) is reacted with ethylamine,dimethylamine or azetidine.
 9. Compound of formula:

in which: n is 1 or 2; W represents an oxygen atom or a sulphur atom; R₁represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; atrifluoromethyl radical; a trifluoromethoxy radical; R₂ represents ahydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; atrifluoromethyl radical; or R₂ is in position -6- of the indol-2-onering and R₁ and R₂ together represent a divalent trimethylene radical;R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy; a trifluoromethoxy radical; R₄ represents a hydrogenatom; a halogen atom; a (C₁-C₂)alkyl; a (C₁-C₂)alkoxy; or R₃ is inposition -2- of the phenyl, R₄ is in position -3- of the phenyl and R₃and R₄ together represent a methylenedioxy radical; R₅ represents anethylamino group; a dimethylamino group; a 1-azetidinyl radical; a(C₁-C₂)alkoxy; as well as the salts thereof with mineral or organicacids, in the form of optically pure isomers or in the form of a mixtureof diastereoisomers or in the form of a racemic mixture. 10.Pharmaceutical composition comprising, as active principle, a compoundaccording to any one of claims 1 to 6 or a pharmaceutically acceptablesolvate and/or hydrate thereof.
 11. Use of a compound according to anyone of claims 1 to 6 or of pharmaceutically acceptable solvates and/orhydrates thereof, for the preparation of medicinal products intended fortreating any pathology in which arginine-vasopressin and/or its V_(1b)receptors or both its V_(1b) receptors and its V_(1a) receptors areinvolved.
 12. Medicinal product, characterized in that it consists of acompound according to any one of claims 1 to 6.